Peptide macrocycles against Acinetobacter baumannii

ABSTRACT

The present invention provides compounds of formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein X 1  to X 8  and R 1  to R 8  are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by  Acinetobacter baumannii.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/336,128, filed on Oct. 27, 2016; which claims priority toInternational Patent Application No. PCT/CN2016/100125, filed on Sep.26, 2016; and European Patent Application No. 15191743.2, filed on Oct.27, 2015. The entire contents of each of the above applications arehereby incorporated herein by reference.

INTRODUCTION

The present invention provides compounds which exhibit activity againstAcinetobacter baumannii, their manufacture, pharmaceutical compositionscomprising them and their use as medicaments for the treatment ofdiseases and infections caused by Acinetobacter baumannii.

In particular, the present invention relates to compounds of formula (I)

-   -   wherein X¹ to X⁸ and R¹ to R⁸ are as described herein, and        pharmaceutically acceptable salts thereof.

BACKGROUND

Acinetobacter baumannii is a Gram-negative, aerobic, nonfermentingbacterium recognized over the last decades as an emergining pathogenwith very limited treatment options.

A. baumannii is considered to be a serious threat by the US Centers forDisease Control and Prevention and belongs to the so called ‘ESKAPE’pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiellapneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa andEnterobacter species & E. coli) that currently cause the majority ofnosocomial infections and effectively “escape” the activity ofantimicrobial agents.

A. baumannii is most often encountered in intensive care units andsurgical wards, where extensive antibiotic use has enabled selection forresistance against all known antimicrobials and where it causesinfections that include bacteremia, pneumonia, meningitis, urinary tractinfection, and wound infection.

A. baumannii has an exceptional ability to upregulate and acquireresistance determinats and shows an environmental persistence thatallows its survival and spread in the nosocomial setting, making thisorganism a frequent cause of outbreaks of infection and an endemic,health care-associated pathogen.

Due to increasing antibiotic resistance to most if not all availabletherapeutic options, Muti-Drug Resistant (MDR) A. baumannii infections,especially those caused by Carbapenem resistant A. baumannii, areextremely difficult or even impossible to treat with high mortality rateas well as increased morbidity and length of stay in intensive careunit.

Acinetobacter baumannii has been defined and still remains “a primeexample of a mismatch between unmet medical needs and the currentantimicrobial research and development pipeline” according to theAntimicrobial Availability Task Force (AATF) of the Infectious DiseasesSociety of America (IDSA). Thus, there is a high demand and need toidentify compounds suitable for the treatment of diseases and infectionscaused by Acinetobacter baumannii.

The present invention provides a novel chemotype (peptide macrocycles)that exhibits activity against drug-susceptible as well asdrug-resistant strains of Acinetobacter baumannii. The molecules havebeen routinely tested against drug susceptible A. baumannii strains(ATCC19606 and ATCC 17978) and in addition over a panel often clinicalisolates. Some representative molecules were selected for in vivoprofiling. Both, the pharmacokinetic profile as well as the efficacy ina mouse septicemia model are indicative of a great potential for furtherdevelopment of the compound class.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety.

The nomenclature used in this Application is based on IUPAC systematicnomenclature, unless indicated otherwise.

AutoNom 2000 (Automatic Nomenclature) for ISIS/Draw was employed togenerate IUPAC chemical names.

Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atomin the structures herein indicates the presence of a hydrogen, unlessindicated otherwise.

The term “moiety” refers to an atom or group of chemically bonded atomsthat is attached to another atom or molecule by one or more chemicalbonds thereby forming part of a molecule.

For example, the variables R¹, R² and R³ of formula (I) refer tomoieties that are attached to the core structure of formula (I) by acovalent bond.

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents.

The term “optional” or “optionally” denotes that a subsequentlydescribed event or circumstance can but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not.

The term “substituent” denotes an atom or a group of atoms replacing ahydrogen atom on the parent molecule.

The term “substituted” denotes that a specified group bears one or moresubstituents. Where any group can carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The term “compound(s) of this invention” and “compound(s) of the presentinvention” refers to compounds as disclosed herein and stereoisomers,tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts)thereof.

When the compounds of the invention are solids, it is understood bythose skilled in the art that these compounds, and their solvates andsalts, may exist in different solid forms, particularly differentcrystal forms, all of which are intended to be within the scope of thepresent invention and specified formulas.

The term, “structurally related substances” denotes substances thatshare a common or core structure of the substance that has biologicalactivity, such as a common pharmacophore or olfactophore. Suchstructurally related substances can differ from each other, however, intheir substituent groups.

The term “pharmaceutically acceptable esters” denotes derivatives of thecompounds of present invention, in which a carboxy group has beenconverted to an ester, wherein carboxy group means —C(O)O—. Methyl-,ethyl-, methoxymethyl-, methylthiomethyl-, and pivaloyloxymethylestersare examples of such suitable esters. The term “pharmaceuticallyacceptable esters” furthermore embraces derivatives of the compounds ofpresent invention in which hydroxy groups have been converted to thecorresponding esters with inorganic or organic acids such as nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid,or p-toluenesulfonic acid, and which are non toxic to living organisms.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes thosepharmaceutically acceptable salts formed with an organic or inorganicbase. Examples of acceptable inorganic bases include sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Salts derived from pharmaceutically acceptable organicnontoxic bases includes salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, and polyamine resins.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. In describing an optically active compound, the prefixes Dand L, or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The substituents attached to thechiral center under consideration are ranked in accordance with theSequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem.Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and(−) are employed to designate the sign of rotation of plane-polarizedlight by the compound, with (−) or L designating that the compound islevorotatory. A compound prefixed with (+) or D is dextrorotatory.

The term “halo”, “halogen”, and “halide” are used interchangeably hereinand denote fluoro, chloro, bromo, or iodo. Particular examples of haloare fluoro and chloro.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. In particular embodiments,alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4carbon atoms. Examples of alkyl include methyl, ethyl, propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Particularexamples of alkyl are methyl, ethyl, isopropyl, n-butyl, sec-butyl andtert-butyl, most particularly methyl and ethyl.

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is analkyl group.

Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, andtert-butoxy. Particular examples of alkoxy is methoxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by same or differenthalogen atoms, particularly fluoro atoms.

Examples of haloalkyl include monofluoro-, difluoro- ortrifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl,2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.The term “perhaloalkyl” denotes an alkyl group where all hydrogen atomsof the alkyl group have been replaced by the same or different halogenatoms. Particular examples of haloalkyl is trifluoromethyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloalkoxyl include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxyor -propoxy, for example 3,3,3-trifluoropropoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy, fluoromethoxy, or trifluoromethoxy. The term“perhaloalkoxy” denotes an alkoxy group where all hydrogen atoms of thealkoxy group have been replaced by the same or different halogen atoms.

The term “hydroxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by a hydroxygroup. Examples of hydroxyalky include hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutylor 2-(hydroxymethyl)-3-hydroxypropyl.

The term “bicyclic ring system” denotes two rings which are fused toeach other via a common single or double bond (annelated bicyclic ringsystem), via a sequence of three or more common atoms (bridged bicyclicring system) or via a common single atom (spiro bicyclic ring system).Bicyclic ring systems can be saturated, partially unsaturated,unsaturated or aromatic. Bicyclic ring systems can comprise heteroatomsselected from N, O and S.

The term “cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consistingof two saturated carbocycles having one or more carbon atoms in common.Particular cycloalkyl groups are monocyclic. Examples for monocycliccycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl orcycloheptyl. Examples for bicyclic cycloalkyl arebicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. Particular cycloalkylis cyclopropyl.

The term “heterocycloalkyl” denotes a monovalent saturated or partlyunsaturated mono- or bicyclic ring system of 3 to 9 ring atoms,comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, theremaining ring atoms being carbon. In particular embodiments,heterocycloalkyl is a monovalent saturated monocyclic ring system of 4to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N,O and S, the remaining ring atoms being carbon. Examples for monocyclicsaturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl,azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples forbicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl,quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturatedheterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl,tetrahydro-pyridinyl, or dihydropyranyl. Particular examples ofheterocycloalkyl are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl and dihydropyranyl.Particular examples of saturated heterocycloalkyl are pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and2-oxa-5-aza-bicyclo[2.2.1]heptyl. Particular examples of partlyunsaturated heterocycloalkyl are dihydropyranyl and dihydroindolyl.

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC—Compendium of ChemicalTerminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). BlackwellScientific Publications, Oxford (1997).

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms. Examples ofaryl moieties include phenyl and naphthyl, most particularly phenyl.Particular aryl substituted by aryl is biphenyl.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl moieties include pyrrolyl, furanyl,thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl,pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl,isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl,benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.Particular examples of heteroaryl are imidazolyl, pyrazolyl, pyrrolyl,isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl andquinolyl. Most particular examples of heteroaryl are pyridinyl andindolyl.

The term “protecting group” denotes the group which selectively blocks areactive site in a multifunctional compound such that a chemicalreaction can be carried out selectively at another unprotected reactivesite in the meaning conventionally associated with it in syntheticchemistry.

Protecting groups can be removed at the appropriat point. Exemplaryprotecting groups are amino-protecting groups, carboxy-protecting groupsor hydroxy-protecting groups.

The term “amino-protecting group” denotes groups intended to protect anamino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy,CBZ), Fmoc (9-Fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), andtrifluoroacetyl. Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nded., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 7; E.Haslam, “Protective Groups in Organic Chemistry”, J. G. W. McOmie, Ed.,Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981. The term “protected amino group” refers to an amino groupsubstituted by an amino-protecting groups.

The term “carboxy-protecting group” denotes groups intended to protect acarboxy group and includes ester groups and heterocycloalkyl groups.Examples of such ester groups include substituted arylalkyl esters,including esters with substituted benzyls, such as 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl,2,2′,4,4′-tetramethoxybenzhydryl, esters with alkyl or substituted alkylsuch as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl(trityl), 4-methoxytrityl, 4,4′-dimethoxytrityl,4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butylthioester, silyl esters such as trimethylsilyl, t-butyldimethylsilylesters, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl,beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and1-(trimethylsilylmethyl)prop-1-en-3-yl. Another example ofcarboxy-protecting groups are heterocycloalkyl groups such as1,3-oxazolinyl. Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nded., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E.Haslam, “Protective Groups in Organic Chemistry”, J. G. W. McOmie, Ed.,Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene,“Protective Groups in Organic Synthesis”, John Wiley and Sons, New York,N.Y., 1981, Chapter 5. The term “protected carboxy group” denotes acarboxy group substituted by a carboxy-protecting group.

The term “hydroxy-protecting group” denotes groups intended to protect ahydroxy group and include ester- and ether-forming groups, in particulartetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g. TBS, TBDPS) groups. Further examples of these groupsare found in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, 2nd ed., John Wiley & Sons, Inc., New York, N.Y.,1991, chapters 2-3; E. Haslam, “Protective Groups in Organic Chemistry”,J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, andT. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley andSons, New York, N.Y., 1981. The term “protected hydroxy group” refers toa hydroxy group substituted by a hydroxy-protecting group.

The term “deprotection” or “deprotecting” denotes the process by which aprotective group is removed after the selective reaction is completed.Deprotecting reagents include acids, bases or hydrogen, in particularpotassium or sodium carbonates, lithium hydroxide in alcoholicsolutions, zinc in methanol, acetic acid, trifluoroacetic acid,palladium catalysts, or boron tribromide.

The term “active pharmaceutical ingredient” (or “API”) denotes thecompound or molecule in a pharmaceutical composition that has aparticular biological activity.

The terms “pharmaceutical composition” and “pharmaceutical formulation”(or “formulation”) are used interchangeably and denote a mixture orsolution comprising a therapeutically effective amount of an activepharmaceutical ingredient together with pharmaceutically acceptableexcipients to be administered to a mammal, e.g., a human in needthereof.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

The terms “pharmaceutically acceptable excipient”, “pharmaceuticallyacceptable carrier” and “therapeutically inert excipient” can be usedinterchangeably and denote any pharmaceutically acceptable ingredient ina pharmaceutical composition having no therapeutic activity and beingnon-toxic to the subject administered, such as disintegrators, binders,fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants,surfactants, carriers, diluents or lubricants used in formulatingpharmaceutical products.

The term “therapeutically effective amount” denotes an amount of acompound or molecule of the present invention that, when administered toa subject, (i) treats or prevents the particular disease, condition ordisorder, (ii) attenuates, ameliorates or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition or disorder described herein. The therapeuticallyeffective amount will vary depending on the compound, the disease statebeing treated, the severity of the disease treated, the age and relativehealth of the subject, the route and form of administration, thejudgement of the attending medical or veterinary practitioner, and otherfactors.

The term “treating” or “treatment” of a disease state includesinhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms, or relieving the disease state,i.e., causing temporary or permanent regression of the disease state orits clinical symptoms.

The term “preventing” or “prevention” of a disease state denotes causingthe clinical symptoms of the disease state not to develop in a subjectthat can be exposed to or predisposed to the disease state, but does notyet experience or display symptoms of the disease state.

The term “amino acid” as used herein denotes an organic moleculepossessing an amino moiety located at a-position to a carboxylic group.Examples of amino acids include: arginine, glycine, omithine, lysine,histidine, glutamic acid, asparagic acid, isoleucine, leucine, alanine,phenylalanine, tyrosine, tryptophane, methionine, serine, proline. Theamino acid employed is optionally in each case the L-form.

In detail, the present invention relates to a compound of formula (I)

wherein:

-   X¹ is C-L¹-R¹¹ or N,-   X² is C-L²-R¹² or N,-   X³ is C-L³-R¹³ or N,-   X⁴ is C-L⁴-R¹⁴ or N, with the proviso that not more than three of    X¹, X², X³ and X⁴ are N;-   X⁵ is C-L⁵-R¹⁵ or N,-   X⁶ is C-L⁶-R¹⁶ or N,-   X⁷ is C-L⁷ R¹⁷ or N,-   X⁸ is C-L⁸-R¹⁸ or N, with the proviso that not more than three of    X⁵, X⁶, X⁷ and X⁸ are N;-   R¹ is —(CH₂)_(m)-heteroaryl or —(CH₂)_(m)-heterocycloalkyl, wherein    heteroaryl is optionally substituted with one or more halo, cyano,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl or C₁₋₇-alkoxy;-   R², R⁴ and R⁶ are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl;-   R³ is —C₁₋₇-alkyl, —(CH₂)_(n)—NR²⁰R²¹, —(CH₂)_(n)—C(O)NR²⁰R²¹ or    —(CH₂)_(n)—O—(CH₂)_(q)—NR²⁰R²¹;-   R⁵ is hydrogen, C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³,    —(CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)—O—(CH₂)_(q)—NR²⁰R²¹,    —(CH₂)_(o)—NH—C(NH)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³,    —(CH₂)_(o)—NH—C(O)—OR²⁶, —(CH₂)_(o)—C₃₋₇-cycloalkyl,    —(CH₂)_(o)-heterocycloalkyl, —(CH₂)_(o)-heteroaryl, —(CH₂)_(o)-aryl,    wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are    optionally substituted by halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,    C₁₋₇-alkoxy or aryl;-   R^(5′) is hydrogen or C₁₋₇-alkyl;-   R⁷ and R⁸ are each individually selected from hydrogen, C₁₋₇-alkyl,    C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and C₁₋₇-alkoxy;-   R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are each individually selected from    hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵,    C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy, —B(OH)₂,    benzyloxy-propynyl (—C≡C—CH₂—O-benzyl), C₃₋₇-cycloalkyl,    heterocycloalkyl, aryl and heteroaryl,    -   wherein heteroaryl is optionally substituted with one        C₁₋₇-haloalkyl or C₁₋₇-alkoxy;-   R¹⁷ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,    —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy,    B(OH)₂, benzyloxy-prop-1-ynyl, C₃₋₇-cycloalkyl, heterocycloalkyl,    aryl and heteroaryl,    -   wherein heterocycloalkyl is optionally substituted with one        —NR²⁴R²⁵,    -   wherein aryl and heteroaryl are optionally substituted with one,        two or three substituents selected from the list of halogen,        cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-hydroxyalkyl, hydroxy,        C₁₋₇-alkoxy, —NR²⁴R²⁵, —SO₂—C₁₋₇-alkyl, —SO₂—NR²⁴R²⁵,        heterocycloalkyl and heterocycloalkyl substituted with        C₁₋₇-alkyl;-   R¹⁸ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,    hydroxy, C₁₋₇-hydroxyalkyl, C₁₋₇-alkoxy, C₁₋₇-haloalkoxy, —NR²⁴R²⁵,    C₁₋₇-alkyl-NR²⁴R²⁵, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl and    heteroaryl,    -   wherein aryl and heteroaryl are optionally substituted with one,        two or three substituents selected from the list of halogen,        cyano, C₁₋₇-alkyl C₁₋₇-haloalkyl, hydroxy, C₁₋₇-alkoxy,        —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, —CO—NH—(CH₂)_(r)—NR²⁴R²⁵,        —CO—NH—(CH₂)_(r)—OH, —CO—NH—(CH₂)_(r)-heterocycloalkyl, —CO—OH,        —O—C₁₋₇-hydroxyalkyl, —O—(CH₂)_(r)—CO—OH, —S02-C₁₋₇-alkyl,        —SO₂—NR²⁴R²⁵, heterocycloalkyl, —O-heterocycloalkyl and        heterocycloalkyl substituted with C₁₋₇-alkyl;-   R²¹ and R²³ are each individually selected from hydrogen and    C₁₋₇-alkyl;-   R²⁴ and R²⁵ are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-hydroxyalkyl, and C₃₋₇-cycloalkyl;-   R²⁶ is hydrogen, C₁₋₇-alkyl or benzyl;-   L¹, L², L³, L⁴, L⁵, L⁶, L⁷ and L⁸ are each individually selected    from a single bond, —C(O)—, —SO₂—, —(CH₂)_(p)—, —CH═CH— and —C≡C—;-   m is 1, 2, 3, or 4;-   n is 1, 2, 3, or 4;-   o is 0, 1, 2, 3, or 4;-   p is 1, 2, 3, or 4;-   q is 1, 2, 3, or 4;-   r is 1, 2, 3, or 4;    -   or a pharmaceutically acceptable salt thereof.

Particular embodiments of the present invention are compounds of formula(I) or a pharmaceutically acceptable salt thereof.

Further, it is to be understood that every embodiment relating to aspecific X¹ to X⁸, R¹ to R²³, n or o as disclosed herein may be combinedwith any other embodiment relating to another X¹ to X⁸, R¹ to R²³, m, nor o as disclosed herein.

A particular embodiment of present invention relates to a compound offormula (I′)

wherein:

-   X¹ is C-L¹-R¹¹ or N,-   X² is C-L²-R¹² or N,-   X³ is C-L³-R¹³ or N,-   X⁴ is C-L⁴-R¹⁴ or N, with the proviso that not more than three of    X¹, X², X³ and X⁴ are N;-   X⁵ is C-L⁵-R¹⁵ or N,-   X⁶ is C-L⁶-R¹⁶ or N,-   X⁷ is C-L⁷ R¹⁷ or N,-   X⁸ is C-L⁸-R¹⁸ or N, with the proviso that not more than three of    X⁵, X⁶, X⁷ and X⁸ are N;-   R¹ is —(CH₂)_(m)-heteroaryl, wherein heteroaryl is optionally    substituted with one or more halo, cyano, C₁₋₇-alkyl,    C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl or C₁₋₇-alkoxy;-   R², R⁴ and R⁶ are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl;-   R³ is —(CH₂)_(n)—NR²⁰R²¹;-   R⁵ is C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³,    —(CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³,    —(CH₂)_(o)—C₃₋₇-cycloalkyl, —(CH₂)_(o)-heterocycloalkyl,    —(CH₂)_(o)-heteroaryl, —(CH₂)_(o)-aryl, wherein cycloalkyl,    heterocycloalkyl, heteroaryl and aryl are optionally substituted by    halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl or C₁₋₇-alkoxy;-   R⁷ and R⁸ are each individually selected from hydrogen, C₁₋₇-alkyl,    C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and C₁₋₇-alkoxy;-   R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each individually    selected from hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,    —NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy, C₃₋₇-cycloalkyl,    heterocycloalkyl, aryl and heteroaryl;-   R²⁰ and R²² are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and —C(═NH)—NH₂;-   R²¹ and R²³ are each individually selected from hydrogen and    C₁₋₇-alkyl;-   R²⁴ and R²⁵ are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl;-   L¹, L², L³, L⁴, L⁵, L⁶, L⁷ and L⁸ are each individually selected    from a single bond, —C(O)—, —SO₂—, —(CH₂)_(p)—, —CH═CH— and —C≡C—;-   m, n, o and p are each individually selected from 1, 2, 3 and 4;

or a pharmaceutically acceptable salt thereof.

A particular embodiment of the present invention relates to a compoundof formula (I) or (I′) wherein:

-   X¹ is CR¹¹ or N,-   X² is CR¹² or N,-   X³ is CR¹³ or N,-   X⁴ is CR¹⁴ or N, with the proviso that not more than two of X¹, X²,    X³ and X⁴ are N;-   X⁵ is CR¹⁵ or N,-   X⁶ is CR¹⁶ or N,-   X⁷ is CR¹⁷ or N,-   X⁸ is CR¹⁸ or N, with the proviso that not more than two of X⁵, X⁶,    X⁷ and X⁸ are N;-   R¹ is —(CH₂)_(m)-heteroaryl or —(CH₂)_(m)-heterocycloalkyl; wherein    heteroaryl is optionally substituted with one or more halo, cyano,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl or C₁₋₇-alkoxy; and    wherein heterocycloalkyl is partly unsaturated;-   R², R⁴ and R⁶ are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl;-   R³ is —C₁₋₇-alkyl, —(CH₂)_(n)—NR²⁰R²¹, —(CH₂)_(n)—C(O)NR²⁰R²¹ or    —(CH₂)_(n)—O—(CH₂)_(q)—NR²⁰R²¹;-   R⁵ is hydrogen, C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³,    —(CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)_(o)—O—(CH₂)_(q)—NR²⁰R²¹,    —(CH₂)_(o)—NH—C(NH)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³,    —(CH₂)_(o)—NH—C(O)—OR²⁶, —(CH₂)_(o)-heterocycloalkyl,    —(CH₂)_(o)-heteroaryl, —(CH₂)_(o)-aryl, wherein cycloalkyl,    heterocycloalkyl, heteroaryl and aryl are optionally substituted by    halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or aryl;-   R⁷ and R⁸ are each individually selected from hydrogen, C₁₋₇-alkyl,    C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and C₁₋₇-alkoxy;-   R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are each individually selected from    hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵,    C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy, —B(OH)₂,    benzyloxy-propynyl, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl and    heteroaryl, wherein heteroaryl is optionally substituted with one    C₁₋₇-haloalkyl or C₁₋₇-alkoxy;-   R¹⁷ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,    —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy,    —B(OH)₂, benzyloxy-propynyl, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl    and heteroaryl,    -   wherein heterocycloalkyl is optionally substituted with one        —NR²⁴R²⁵,    -   wherein aryl and heteroaryl are optionally substituted with one,        two or three substituents selected from the list of halogen,        cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-hydroxyalkyl, hydroxy,        C₁₋₇-alkoxy, —NR²⁴R²⁵, —SO₂—C₁₋₇-alkyl, —SO₂—NR²⁴R²⁵,        heterocycloalkyl and heterocycloalkyl substituted with        C₁₋₇-alkyl;-   R¹⁸ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,    hydroxy, C₁₋₇-hydroxyalkyl, C₁₋₇-alkoxy, C₁₋₇-haloalkoxy, —NR²⁴R²⁵,    C₁₋₇-alkyl-NR²⁴R²⁵, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl and    heteroaryl,    -   wherein aryl and heteroaryl are optionally substituted with one,        two or three substituents selected from the list of halogen,        cyano, C₁₋₇-alkyl C₁₋₇-haloalkyl, hydroxy, C₁₋₇-alkoxy,        —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, —CO—NH—(CH₂)_(r)—NR²⁴R²⁵,        —CO—NH—(CH₂)_(r)—OH, —CO—NH—(CH₂)_(r)-heterocycloalkyl, —CO—OH,        —O—C₁₋₇-hydroxyalkyl, —O—(CH₂)_(r)—CO—OH, —SO₂—C₁₋₇-alkyl,        —SO₂—NR²⁴R²⁵, heterocycloalkyl, —O-heterocycloalkyl and        heterocycloalkyl substituted with C₁₋₇-alkyl;-   R²⁰ and R²² are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and —C(═NH)—NH₂;-   R²¹ and R²³ are each individually selected from hydrogen and    C₁₋₇-alkyl;-   R²⁴ and R²⁵ are each individually selected from hydrogen,    C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-hydroxyalkyl, and C₃₋₇-cycloalkyl;-   R²⁶ is hydrogen, C₁₋₇-alkyl or benzyl;-   m, n, o, p, q and r are each individually selected from 1, 2, 3 and    4;

or a pharmaceutically acceptable salt thereof.

A particular embodiment of the present invention relates to a compoundof formula (Ia)

wherein

X¹ to X⁸, and R² to R⁸ are as defined herein;

R⁹ is hydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy,C₁₋₇-haloalkoxy and C₃₋₇-cycloalkyl;

R¹⁰ is hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, or C₃₋₇-cycloalkyl;

R¹⁹ is hydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy,C₁₋₇-haloalkoxy and C₃₋₇-cycloalkyl;

or a pharmaceutically acceptable salt thereof.

A particular embodiment of the present invention relates to a compoundof formula (Ib)

wherein X¹, X⁴, R², R¹⁵, R¹⁷, R¹⁸ and R⁹ are as defined herein and Y is—CH₂— or —CO—; or a pharmaceutically acceptable salt thereof.

A particular embodiment of the present invention relates to a compoundof formula (Ic)

wherein X¹, X⁴, R², R¹⁵, R¹⁷, R¹⁸ and R⁹ are as defined herein and Y is—CH₂— or —CO—; or a pharmaceutically acceptable salt thereof.

In a particular embodiment of the present invention X¹ is N or CR¹¹;particularly N, CH or C-halo; more particularly N, CH or CF; mostparticularly CH.

In a particular embodiment of the present invention X² is N or CR¹²;particularly N, CH, C-halo, C—CH₂—NH₂, C-aryl or C-heteroaryl;particularly N, CH, CF, CBr, C—CH₂—NH₂, C-phenyl or C-pyridinyl; moreparticularly CH or CF; most particularly CH.

In a particular embodiment of the present invention X³ is N or CR¹³;particularly N, CH, C-halo or C-aryl; more particularly N, CH, CBr,C-phenyl; most particularly CH.

In a particular embodiment of the present invention X⁴ is N or CR¹⁴,particularly N or CH, most particularly CH.

In a particular embodiment of the present invention X⁵ is N or CR¹⁵;particularly N, CH, C-halo, C—C₁₋₇-alkyl, C—C₁₋₇-haloalkyl,C-heterocycloalkyl, C-aryl, C-heteroaryl, C-heteroaryl substituted withone C₁₋₇-haloalkyl or C-heteroaryl substituted with one C₁₋₇-alkoxy;more particularly N, CH, CF, CCl, CCH₃, CF₃, C-morpholinyl, C-phenyl,C-pyridinyl, C-pyridinyl substituted with CF₃ or C-pyridinyl substitutedwith methoxy; even more particularly CH, CCl, CCH₃ or CCF₃; mostparticularly CH or CCl.

In a particular embodiment of the present invention X⁶ is N or CR¹⁶;particularly CH, C-halo, C—C₁₋₇-alkyl, C—C₁₋₇-haloalkyl, C-aryl orC-heterocycloalkyl; more particularly N, CH, CF, CCl, CCH₃, CCF₃,C-phenyl or C-morpholinyl; most particularly CH.

In a particular embodiment of the present invention X⁶ is N.

In a particular embodiment of the present invention X⁷ is N or CR¹⁷.

In a particular embodiment of the present invention X⁷ is N, CH, C-halo,C-cyano, C—C₁₋₇-alkyl, C—C₁₋₇-haloalkyl, C—NH₂, C—C₁₋₇-alkoxy, C—B(OH)₂,C—C≡C—CH₂—O—CH₂-aryl, C-aryl, C-heteroaryl, or C-heterocycloalkyl;wherein aryl is optionally substituted with one substituent selectedfrom halo, cyano, SO₂—C₁₋₇-alkyl and SO₂—NH₂; wherein heteroaryl isoptionally substituted with one or two substituents selected from halo,cyano, C₁₋₇-alkyl, NH₂, hydroxy, C₁₋₇-alkoxy, SO₂—C₁₋₇-alkyl,heterocycloalkyl and C₁₋₇-alkyl-heterocycloalkyl; and whereinheterocycloalkyl is optionally substituted with one NH₂.

In a particular embodiment of the present invention X⁷ is N, CH, CF, Cl,CBr, C-cyano, C-methyl, C-ethyl, C-isopropyl, C-tert-butyl, CCF₃, CNH₂,C-methoxy, C—B(OH)₂, C—C≡C—CH₂—O—CH₂-phenyl, C-phenyl, C-heteroaryl, orC-heterocycloalkyl;

wherein phenyl is optionally substituted with one substituent selectedfrom halo, cyano, SO₂—C₁₋₇-alkyl and SO₂—NH₂,

wherein heteroaryl is selected from the list of imidazolyl, pyrazolyl,pyrrolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyland wherein heteroaryl is optionally substituted with one or twosubstituents selected from halo, cyano, C₁₋₇-alkyl, NH₂, hydroxy,C₁₋₇-alkoxy, SO₂—C₁₋₇-alkyl, heterocycloalkyl andC₁₋₇-alkyl-heterocycloalkyl; andwherein heterocycloalkyl is pyrrolidinyl optionally substituted with oneNH₂, morpholinyl 2-oxa-5-aza-bicyclo[2.2.1]heptyl, and3,6-dihydro-2H-pyranyl.

In a particular embodiment of the present invention X⁷ is CH, C-halo,C—C₁₋₇-haloalkyl, or C—C₁₋₇-alkoxy.

In a particular embodiment of the present invention X⁷ is CH, CCl, CCF₃or C-methoxy.

In a particular embodiment of the present invention X⁸ is N or CR¹⁸.

In a particular embodiment of the present invention X⁸ is N, CH, C-halo,C—C₁₋₇-haloalkyl, C-diC₁₋₇-alkylamino, C-aryl, C-heteroaryl, orC-heterocycloalkyl; wherein aryl is optionally substituted with onesubstituent selected from C₁₋₇-alkyl-NH₂, —CO—NH—(CH₂)₂—N(CH₃)₂,—CO—NH—(CH₂)₂—OH, —CO—NH—(CH₂)₂-heterocycloalkyl, —CO—OH,—O—C₁₋₇-hydroxyalkyl, —O—CH₂—CO—OH, —SO₂—C₁₋₇-alkyl, —SO₂—NH₂,—SO₂—NH(CH₂CH₂OH), heterocycloalkyl, and —O— heterocycloalkyl; andwherein heteroaryl is optionally substituted with one substituentselected from halo, C₁₋₇-alkyl, NH₂ and hydroxy.

In a particular embodiment of the present invention X⁸ is N, CH, CF,CCl, CBr, CCF₃, CN(CH₃)₂, C-phenyl, C-pyridinyl, or C-morpholinyl;wherein phenyl is optionally substituted with one substituent selectedfrom —CH₂—NH₂, —CH₂—CH₂—NH₂, —CO—NH—(CH₂)₂—N(CH₃)₂, —CO—NH—(CH₂)₂—OH,—CO—NH—(CH₂)₂-morpholinyl, —CO—OH, —O-(2,3-dihydroxy-propoxy),—O—CH₂—CO—OH, —SO₂—CH₃, —SO₂—NH₂, —SO₂—NH(CH₂CH₂OH), piperidinyl,piperazinyl, and —O— piperidinyl; and wherein pyridinyl is optionallysubstituted with one substituent selected from fluoro, methyl, NH₂ andhydroxy.

In a particular embodiment of the present invention X⁸ is CH, C-halo,C—C₁₋₇-haloalkyl, C-aryl or C-heteroaryl; wherein aryl is optionallysubstituted with one substituent selected from —CO—OH, —O—CH₂—CO—OH,—SO₂—C₁₋₇-alkyl, —SO₂—NH₂ and —SO₂—NH(CH₂CH₂OH); and wherein heteroarylis optionally substituted with one substituent selected from NH₂ andhydroxy.

In a particular embodiment of the present invention X⁸ is CH, CCl, CCF₃,C-phenyl or C-pyridinyl; wherein phenyl is optionally substituted withone substituent selected from —CO—OH, —O—CH₂—CO—OH, —SO₂—CH₃ and—SO₂—NH₂; and wherein pyridinyl is optionally substituted with onesubstituent selected from NH₂ and hydroxy.

In a particular embodiment of the present invention R¹ is—(CH₂)_(m)-heteroaryl or —(CH₂)_(m)-heterocycloalkyl, wherein heteroarylis monocyclic or bicyclic, particularly bicyclic, and is optionallysubstituted with one or more halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl,C₃₋₇-cycloalkyl or C₁₋₇-alkoxy; and wherein heterocycloalkyl is partlyunsaturated.

In a particular embodiment of the present invention R¹ is—(CH₂)_(m)-indolyl, —(CH₂)_(m)-quinolyl, or —(CH₂)_(m)-dihydroindolyl,wherein indolyl, quinolyl and dihydroindolyl are optionally substitutedwith one or more halo or C₁₋₇-alkyl.

In a particular embodiment of the present invention R¹ is indolylmethyloptionally substituted with one or two substituents selected fromfluoro, chloro and methyl or R¹ is 2,3-dihydro-indolmethyl or R¹ isquinolylmethyl.

In a particular embodiment of the present invention R¹ is1H-indol-3-ylmethyl, 1-methyl-1H-indol-3-ylmethyl,2-methyl-1H-indol-3-ylmethyl, 5-fluoro-1H-indol-3-ylmethyl,5-chloro-1H-indol-3-ylmethyl, 6-chloro-1H-indol-3-ylmethyl,6-chloro-1-methyl-1H-indol-3-ylmethyl, quinolin-2-ylmethyl or2,3-dihydro-1H-indol-3-ylmethyl.

In a particular embodiment of the present invention R¹ is1H-indol-3-ylmethyl or 2-methyl-1H-indol-3-ylmethyl.

In a particular embodiment of the present invention R² is hydrogen orC₁₋₇-alkyl, more particularly hydrogen, methyl or ethyl; mostparticularly methyl or ethyl.

In a particular embodiment of the present invention R³ is butyl,amino-propyl, amino-butyl, methylamino-butyl, propionamide oramino-ethoxymethyl.

In a particular embodiment of the present invention R³ is butyl,3-amino-propyl, 4-amino-butyl, 4-methylamino-butyl, propionamide or2-amino-ethoxymethyl.

In a particular embodiment of the present invention R³ is 3-amino-propylor 4-amino-butyl; most particularly 4-amino-butyl.

In a particular embodiment of the present invention R⁴ is hydrogen.

In a particular embodiment of the present invention R⁵ is hydrogen,C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³,—(CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)_(o)—O—(CH₂)_(q)—NR²⁰R²¹,—(CH₂)_(o)—NH—C(NH)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³,—(CH₂)_(o)—NH—C(O)—OR²⁶, —(CH₂)_(o)-heterocycloalkyl,—(CH₂)_(o)-heteroaryl, —(CH₂)_(o)-aryl, wherein heterocycloalkyl,heteroaryl and aryl are optionally substituted by halo, cyano,C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or aryl.

In a particular embodiment of the present invention R⁵ is hydrogen,methyl, isopropyl, isobutyl, hydroxy-methyl, hydroxy-ethyl,hydroxy-propyl, amino-propyl, amino-butyl, methylamino-butyl, acetamide,propionamide, N-methyl-propionamide, amino-ethoxymethyl, ureyl-methyl,guanidiyl-methyl, benzylcarboxy-amino-propyl, piperidinyl,pyridinyl-methyl, methylimidazolyl-methyl, biphenyl-methyl ornaphthalenyl-methyl.

In a particular embodiment of the present invention R⁵ is—(CH₂)_(o)—NR²²R²³ or —(CH₂)_(o)—C(O)—NR²²R²³.

In a particular embodiment of the present invention R⁵ is 3-amino-propylor propionamide.

In a particular embodiment of the present invention R^(5′) is hydrogenor methyl, most particularly hydrogen.

In a particular embodiment of the present invention R⁶ is hydrogen ormethyl, most particularly hydrogen.

In a particular embodiment of the present invention R⁷ is hydrogen ormethyl, most particularly hydrogen.

In a particular embodiment of the present invention R⁸ is hydrogen orC₁₋₇-alkyl; more particularly hydrogen or methyl; most particularlyhydrogen.

In a particular embodiment of the present invention R⁹ is hydrogen orC₁₋₇-alkyl; more particularly hydrogen or methyl; most particularlyhydrogen.

In a particular embodiment of the present invention R¹⁰ is hydrogen orC₁₋₇-alkyl; more particularly hydrogen or methyl; most particularlyhydrogen.

In a particular embodiment of the present invention R¹¹ is hydrogen orhalo; more particularly hydrogen or fluoro; most particularly hydrogen.

In a particular embodiment of the present invention R¹² is hydrogen,halo, C₁₋₇-alkyl-NR²⁴R²⁵, aryl or heteroaryl; more particularlyhydrogen, fluoro, bromo, aminomethyl, phenyl or pyridinyl; mostparticularly hydrogen.

In a particular embodiment of the present invention R¹³ is hydrogen,halo or aryl; more particularly hydrogen, bromo or phenyl; mostparticularly hydrogen.

In a particular embodiment of the present invention R¹⁴ is hydrogen.

In a particular embodiment of the present invention R¹⁵ is hydrogen,halo, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, heterocycloalkyl, aryl or heteroaryl,wherein heteroaryl is optionally substituted with one C₁₋₇-haloalkyl orC₁₋₇-alkoxy.

In a particular embodiment of the present invention R¹⁵ is hydrogen,fluoro, chloro, methyl, CF₃, morpholinyl, phenyl or pyridinyl, whereinpyridinyl is optionally substituted with CF₃ or methoxy.

In a particular embodiment of the present invention R¹⁵ is hydrogen,

In a particular embodiment of the present invention R¹⁶ is hydrogen,halo, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, heterocycloalkyl or aryl.

In a particular embodiment of the present invention R¹⁶ is hydrogen,fluoro, chloro, bromo, methyl, CF₃, morpholinyl or phenyl.

In a particular embodiment of the present invention R¹⁶ is hydrogen.

In a particular embodiment of the present invention R¹⁷ is hydrogen,halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵,C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, —B(OH)₂, benzyloxy-propynyl,heterocycloalkyl, aryl or heteroaryl, wherein heterocycloalkyl isoptionally substituted with one amino, wherein aryl is optionallysubstituted with one halo, cyano, —SO₂—C₁₋₇-alkyl, or —SO₂—NR²⁴R²⁵, andwherein heteroaryl is optionally substituted with one or twosubstituents selected from the list of halogen, cyano, C₁₋₇-alkyl,C₁₋₇-hydroxyalkyl, hydroxy, C₁₋₇-alkoxy, —NR²⁴R²⁵, —SO₂—C₁₋₇-alkyl,heterocycloalkyl and heterocycloalkyl substituted with C₁₋₇-alkyl.

In a particular embodiment of the present invention R¹⁷ is hydrogen,fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, tertbutyl, CF₃,amino, methoxy, B(OH)₂, benzyloxy-propynyl, pyrrolidinyl,amino-pyrrolidinyl, morpholinyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,dihydropyranyl, phenyl, chloro-phenyl, cyano-phenyl,methylsulfonyl-phenyl, aminosulfonyl-phenyl, imidazolyl,methyl-imidazolyl, methyl-pyrazolyl, dimethyl-pyrazolyl, pyrrolyl,dimethyl-isoxazolyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl,chloro-pyridinyl, cyano-pyridinyl, methyl-pyridinyl, amino-pyridinyl,dimethylamino-pyridinyl, hydroxy-pyridinyl, methoxy-pyridinyl,methylsulfonyl-pyridinyl, morpholinyl-pyridinyl,methylpiperazinyl-pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl.

In a particular embodiment of the present invention R¹⁷ is hydrogen,halogen, C₁₋₇-haloalkyl, or C₁₋₇-alkoxy.

In a particular embodiment of the present invention R¹⁷ is hydrogen,chloro, CF₃, or methoxy.

In a particular embodiment of the present invention R¹⁸ is hydrogen,halogen, C₁₋₇-haloalkyl, —NR²⁴R²⁵, heterocycloalkyl, aryl or heteroaryl,

wherein aryl is optionally substituted with one substituent selectedfrom the list of C₁₋₇-alkyl-NR²⁴R²⁵, —CO—NH—(CH₂)_(r)—NR²⁴R²⁵,—CO—NH—(CH₂)_(r)—OH, —CO—NH—(CH₂)_(r)-heterocycloalkyl, —CO—OH, —O—C₁7-hydroxyalkyl, —O—(CH₂)_(r)—CO—OH, —SO₂—C₁₋₇-alkyl, —SO₂—NR²⁴R²⁵,heterocycloalkyl, and —O-heterocycloalkyl,and wherein heteroaryl is optionally substituted with one substituentselected from halo, C₁₋₇-alkyl, amino and hydroxy.

In a particular embodiment of the present invention R¹⁸ is hydrogen,fluoro, chloro, bromo, CF₃, dimethylamino, morpholinyl, phenyl orpyridinyl,

wherein phenyl is optionally substituted with one substituent selectedfrom the list of amino-methyl, amino-ethyl, —CO—NH—(CH₂)₂—N(CH₃)₂,—CO—NH—(CH₂)₂—OH, —CO—NH—(CH₂)₂-morpholinyl, —CO—OH,2,3-dihydroxy-propoxy, —O—CH₂—CO—OH, —SO₂-methyl, —SO₂—NH₂,—SO₂—NH(hydroxyethyl), piperidinyl, piperazinyl, and piperidinyloxy,and wherein heteroaryl is optionally substituted with one substituentselected from fluoro, methyl, amino and hydroxy.

In a particular embodiment of the present invention R¹⁸ is hydrogen,chloro, CF₃, phenyl or pyridinyl,

wherein phenyl is optionally substituted with one substituent selectedfrom the list of —CO—OH, —O—CH₂—CO—OH, —SO₂-methyl, —SO₂—NH₂, and—SO₂—NH(hydroxyethyl), and wherein heteroaryl is optionally substitutedwith one substituent selected from amino and hydroxy.

In a particular embodiment of the present invention R¹⁹ is hydrogen orhalo, more particularly hydrogen or chloro; most particularly hydrogen.

In a particular embodiment of the present invention R²⁰ is hydrogen ormethyl, particularly hydrogen.

In a particular embodiment of the present invention R²¹ is hydrogen.

In a particular embodiment of the present invention R²² is hydrogen,C₁₋₇-alkyl and —C(═NH)—NH₂; more particularly hydrogen, methyl or—C(═NH)—NH₂; most particularly hydrogen.

In a particular embodiment of the present invention R²³ is hydrogen.

In a particular embodiment of the present invention R²⁴ is hydrogen.

In a particular embodiment of the present invention R²⁵ is hydrogen.

In a particular embodiment of the present invention R²⁶ is hydrogen,methyl or benzyl.

In a particular embodiment of the present invention m is 1.

In a particular embodiment of the present invention n is 1, 3 or 4,particularly 4.

In a particular embodiment of the present invention o is 0, 1, 3 or 4,particularly 3.

In a particular embodiment of the present invention p is 1, 2, 3 or 4.

In a particular embodiment of the present invention q is 2.

In a particular embodiment of the present invention r is 1 or 2,particularly 2.

A particular embodiment of the present invention relates to a compoundof formula (I),

-   -   (I′), (Ia), (Ib) or (Ic), wherein:    -   X¹ is CR¹¹;    -   X² is CR¹²;    -   X³ is CR¹³;    -   X⁴ is N;    -   X⁵ is CR¹⁵;    -   X⁶ is CR¹⁶ or X⁶ is N;    -   R¹ is —(CH₂)_(m)-indolyl, wherein indolyl is optionally        substituted with one or more    -   halo or C₁₋₇-alkyl;    -   R² is hydrogen or C₁₋₇-alkyl;    -   R³ is 3-amino-propyl or 4-amino-butyl;    -   R⁴ is hydrogen;    -   R⁵ is —(CH₂)_(o)—NR²²R²³ or piperidinyl;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen;    -   R⁸ is hydrogen or C₁₋₇-alkyl;    -   R⁹ is hydrogen or C₁₋₇-alkyl;    -   R¹⁰ is hydrogen or C₁₋₇-alkyl;    -   R¹¹ is hydrogen or halo;    -   R¹² is hydrogen or halo;    -   R¹³ is hydrogen;    -   R¹⁴ is hydrogen;    -   R¹⁵ is hydrogen, halo, C₁₋₇-alkyl or halo-C₁₋₇-alkyl;    -   R¹⁶ is hydrogen, halo, C₁₋₇-alkyl or halo-C₁₋₇-alkyl;    -   R¹⁷ is hydrogen, halo, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, C₁₋₇-alkoxy        or aryl;    -   R¹⁸ is hydrogen, halo or halo-C₁₋₇-alkyl;    -   R¹⁹ is hydrogen or halo;    -   R²⁰ is hydrogen;    -   R²¹ is hydrogen;    -   R²² is hydrogen, C₁₋₇-alkyl and —C(═NH)—NH₂;    -   R²³ is hydrogen;    -   m is 1;    -   n is 3 or 4; and    -   o is 1, 3 or 4;    -   or a pharmaceutically acceptable salt thereof.

A particular embodiment of the present invention relates to a compoundof formula (Ia),

-   -   wherein    -   X¹ is CH or C-halo;    -   X² is CH or C-halo;    -   X³ is CH;    -   X⁴ is CH or N;    -   X⁵ is CH, C-halo, C—C₁₋₇-alkyl or C—C₁₋₇-haloalkyl;    -   X⁶ is N, CH, C-halo, C—C₁₋₇-alkyl or C—C₁₋₇-haloalkyl;    -   X⁷ is CH, C-halo, C—C₁₋₇-alkyl, C—C₁₋₇-haloalkyl, C—C₁₋₇-alkoxy        or C-aryl;    -   X⁸ is CH, C-halo or C—C₁₋₇-haloalkyl;    -   R¹ is indolylmethyl optionally substituted with one or two        substituents selected from    -   chloro and methyl;    -   R² is hydrogen or C₁₋₇-alkyl;    -   R³ is 3-amino-propyl or 4-amino-butyl;    -   R⁴ is hydrogen;    -   R⁵ is 3-amino-propyl, 4-methylamino-butyl, guanidinyl-methyl or        piperidinyl;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen;    -   R⁸ is hydrogen or C₁₋₇-alkyl;    -   R⁹ is hydrogen or C₁₋₇-alkyl;    -   R¹⁰ is hydrogen or C₁₋₇-alkyl;    -   R¹⁹ is hydrogen or halo;

or a pharmaceutically acceptable salt thereof.

Particular compounds of formula (I), (I′), (Ia), (Ib) or (Ic) of thepresent invention are those selected from the group consisting of:

-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15,18-Bis-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-12-(1H-indol-3-ylmethyl)-13-methyl-18-piperidin-4-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   N-[(11S,14S,17S)-14-(4-Amino-butyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-ylmethyl]-guanidine;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-5,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-5-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(6-chloro-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-methyl-12-(1-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(6-chloro-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (9S,12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-9,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6,7-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-7-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,7-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-7-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-7-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,7-difluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-22-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22,23-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22,25-difluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-6,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-ethyl-12-(1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-6-methoxy-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-13-ethyl-12-(1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-4-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-4-chloro-12-(1H-indol-3-ylmethyl)-3-methyl-18-(4-methylamino-butyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16,25-dimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,13-dimethyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (9S,12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-9,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-23-methoxy-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-fluoro-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-ethyl-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-tert-butyl-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-methoxy-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-isopropyl-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-16-ethyl-17-(1H-indol-3-ylmethyl)-25-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-(3-methyl-3H-imidazol-4-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-pyridin-3-ylmethyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-23-phenyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-bromo-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-23,25-bis-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-morpholin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11,16-dimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11-isopropyl-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-hydroxymethyl-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11-isobutyl-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(2-methoxy-pyridin-4-yl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-((S)-1-hydroxy-ethyl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11,11,16-trimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-6-methyl-11-naphthalen-2-ylmethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-naphthalen-1-ylmethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   {(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecin-18-yl}boronic    acid;-   (12S,15S,18S)-15-(3-Amino-propyl)-18-biphenyl-4-ylmethyl-12-(1H-indol-3-ylmethyl)-19-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(2-amino-ethoxymethyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-11,14-Bis-(2-amino-ethoxymethyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(2-Amino-ethoxymethyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11R,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11R,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   2-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-6-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-acetamide;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrrolidin-1-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(5-fluoro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-quinolin-2-ylmethyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15,18-Bis-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-3-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(2-methoxy-pyridin-4-yl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23    exaen-11-yl]-propionamde;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(5-chloro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(2,3-dihydro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-6-methyl-23-morpholin-4-yl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,6-dihydro-2H-pyran-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   {3-[(11S,14S,17S)-14-(4-Amino-butyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propyarbamic    acid benzyl ester;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-6-(2-chloro-phenyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-pyridin-3-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-pyridin-4-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-(1-methyl-1H-pyrazol-3-yl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-6-methyl-23-(2-methyl-pyridin-4-yl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrazin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-morpholin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridazin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15-18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-1,4-dichloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-3-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-25-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-12-methyl-18-(trifluoromethyl)-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-1-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-chloro-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   3-[(11S,14S,17S)-14-(3-Amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   3-[(11S,14S,17S)-11-(3-Amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-25-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-14-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-morpholin-4-yl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-pyridin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-chloro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(6-dimethylamino-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(2-methylpyridin-4-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-23-(3,5-dimethyl-isoxazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-methoxy-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(5-methanesulfonyl-pyridin-3-yl)-6-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(3-amino-pyrrolidin-1-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,5-dimethyl-1H-pyrazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-5-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-23-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-118-(6-methylpyridin-3-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-3-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   [(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-6-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-ylmethyl]-urea;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-chloro-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-fluoro-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-7-(1H-indol-3-ylmethyl)-6-methyl-12,15,18-trioxo-23-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-23-carbonitrile;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,5-dimethyl-isoxazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(3-benzyloxy-prop-1-ynyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-phenyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-9-methyl-2-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-9-methyl-4-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(pyridin-3-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(pyridin-4-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-1-(2-methoxypyridin-4-yl)-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-bromo-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(2-(trifluoromethyl)pyridin-4-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(5-methanesulfonyl-pyridin-3-yl)-16-methyl-7-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-6,7,9,10,12,13,15,16-octahydro-12-methyl-13-[(2-methyl-1H-indol-3-yl)methyl]-18-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]pyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-morpholino-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-(2-methoxypyridin-4-yl)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-23-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-23-pyridin-3-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2,6-difluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3(8),4,6,22,24-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-N-methyl-propionamide;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-23-yl]-benzonitrile;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrimidin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaen-23-yl]-benzenesulfonamide;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(2-methylpyridin-4-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-23-(4-aminomethyl-phenyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-(2-methoxypyridin-4-yl)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-morpholino-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-24-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-24-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(2-amino-pyridin-4-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-112,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaen-22-yl]-benzenesulfonamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-22-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-3-fluoro-12-methyl-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-imidazol-1-yl-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-23-yl]-pyridine-2-carbonitrile;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-22-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(1H-pyrrol-3-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-23-carbonitrile;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(4-methanesulfonyl-phenyl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-117-(2-methyl-1H-indol-3-ylmethyl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-23-yl]-benzenesulfonamide;-   (7S,10S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-3-bromo-12-methyl-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (7S,10S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-17-(dimethylamino)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   (7S,10S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-117-(pyridin-3-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-benzoic    acid;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-[4-(2,3-dihydroxy-propoxy)-phenyl]-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   {4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-phenoxy}-acetic    acid;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-[4-(piperidin-4-yloxy)-phenyl]-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-22-(4-aminomethyl-phenyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-22-[3-(2-amino-ethyl)-phenyl]-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-piperazin-1-yl-phenyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzamide;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-dimethylamino-ethyl)-benzamide;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-112,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-piperidin-4-yl-phenyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-11-(3-Amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-14-(4-methylamino-butyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-(3-hydroxy-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-11-(3-Amino-propyl)-14-butyl-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;

and pharmaceutically acceptable salts thereof.

More particular compounds of formula (I), (I′), (Ia), (Ib) or (Ic) ofthe present invention are those selected from the group consisting of:

-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-6-methoxy-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-4-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-2,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-16-ethyl-117-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-7-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaen-22-yl]-benzenesulfonamide;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-22-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1    (21),3,5,7,22,24-hexaene-12,15,18-trione;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-benzoic    acid;-   {4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-phenoxy}-acetic    acid;-   4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide;

and pharmaceutically acceptable salts thereof.

Most particular compounds of formula (I), (I′), (Ia), (Ib) or (Ic) ofthe present invention are those selected from the group consisting of:

-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23,25-dichloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;    and pharmaceutically acceptable salts thereof.

Further particular compounds of formula (I), (I′), (Ia), (Ib) or (Ic) ofthe present invention are those selected from the group consisting of:

-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-6-methoxy-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-4-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23,25-dichloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-22,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;-   (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione;    and pharmaceutically acceptable salts thereof.

Manufacturing Processes

Compounds of formula (I), (I′), (Ia), (Ib) or (Ic) and pharmaceuticallyacceptable salts thereof as defined above can be prepared followingstandard methods known in the art.

1. General Synthesis of the Tether

The tether intermediate of formula (III) can be prepared followingstandard methods known in the art, particularly according to methods asdescribed in the examples (e.g. PG=Fmoc).

2. General Synthesis of the Tripeptide

The tripeptide of formula (IV) can be prepared following standardmethods known in the art.

The tripeptide sequence can for example be synthesized viastate-of-the-art solid-phase peptide synthesis (SPPS) protocols (e.g.Fmoc-chemistry) as follows:

-   -   a) A resin (e.g. 2-Cl-Trityl resin) as solid support is loaded        with the first N-protected amino acid and Hünig's base        (N,N-Diisopropylethylamine or DIPEA) followed by cleavage of the        protecting group.    -   b) A second N-protected amino acid is coupled with a coupling        reagent and Hünig's base followed by cleavage of the protecting        group (e.g. Fmoc).    -   c) A third N-protected amino acid is coupled with a coupling        reagent and Hünig's base followed by cleavage of the protecting        group.

In case N-methylated amino acids are present in the compound of formula(IV), the alkylation may be performed on the solid phase. After theappropriate step of the SPPS, the terminal amine is protected in a firststep e.g. by swelling the resin in tetrahydrofurane (THF) and additionof Hünig's base and 2-nitrobenzene-1-1sulfonylchloride (Nbs). In thesecond step, methyl-4-nitrobenzenesulfonate together with7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene can be added to the resinin dimethylfurane (DMF). For removal of the2-nitrobenzene-1-1sulfonamide protecting group,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can be added to the resin inDMF followed by addition of mercaptoethanol.

In a particular embodiment, the solid support is a2-Chlor-tritylchloride resin.

In a particular embodiment, the N-protected amino acids are protectedwith 9-fluorenylmethyloxycarbonyl (Fmoc).

In a particular embodiment, the resin is loaded in step a) with 0.1-1.0eq of the first amino acid and excess Hünig's base in dichloromethane(DCM).

In a particular embodiment, the resin is thoroughly washed after thecoupling reaction in step a) with dimethylformamide (DMF) anddichloromethane (DCM).

In a particular embodiment, the Fmoc protecting group is cleaved off instep a) with a mixture of 50% Piperidine in DCM/DMF (1:1).

In a particular embodiment, the resin is thoroughly washed after thedeprotection in step a) with DMF, DCM and Methanol (MeOH) followed bydrying under vacuum and weighing.

In a particular embodiment, the coupling reagent in step b) isMukaiyama's reagent (2-chloro-1-methylpyridinium iodide).

In a particular embodiment, the second amino acid in step b) is coupledwith 4 eq of Mukaiyama's reagent as coupling reagent and 6 eq of Hünig'sbase in DMF/DCM (1:1).

In a particular embodiment, the resin is thoroughly washed after thecoupling reaction in step b) with dimethylformamide (DMF) anddichloromethane (DCM).

In a particular embodiment, the Fmoc protecting group is cleaved off instep b) with a mixture of 50% Piperidine in DCM/DMF (1:1).

In a particular embodiment, the resin is thoroughly washed after thedeprotection in step b) with DMF and DCM followed by drying under vacuumand weighing.

In a particular embodiment, the coupling reagent in step c) is HATU(1-[bis(dimethyl-amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate).

In a particular embodiment, the third amino acid in step c) is coupledwith 4 eq of HATU as coupling reagent and 6 eq of Hünig's base inDMF/DCM (1:1).

In a particular embodiment, the resin is thoroughly washed after thecoupling reaction in step c) with dimethylformamide (DMF) anddichloromethane (DCM).

In a particular embodiment, the Fmoc protecting group is cleaved off instep c) with a mixture of 20% Piperidine in DMF.

In a particular embodiment, the resin is thoroughly washed after thedeprotection in step c) with DMF and DCM followed by drying under vacuumand weighing.

3. General Synthesis for the Coupling of the Tripeptide to the Tether

The compound of formula (I) can be obtained starting from the compoundsof formula (III) and of formula (IV) according to Scheme 1.

The tether aldehyde or ketone of formula (III) is dissolved in a mixtureof N-methyl-2-pyrrolidone (NMP), trimethyl orthoformate (TMOF) andacetic acid (AcOH) and the resin comprising the tripeptide of formula(IV) is added to the solution. After agitation of the mixture, sodiumcyanoborohydride (NaCNBH₃) is added to provide a compound of formula(II).

After the Borch reaction, the protecting group (PG) on the tether iscleaved off, e.g. with a mixture of 20% Piperidine in DMF. The resin onthe tripeptide can be cleaved e.g. by addition of 20%hexafluoroisopropanol (HFIP) in DCM and filtered off. The compound offormula (I) is finally obtained through cyclisation of the cleavedcompound of formula (II) using HATU and Hünig's base followed by globaldeprotection of remaining protected amine groups.

A particular embodiment of the invention relates to a process for themanufacture of a compound of formula (I) comprising the steps of:

a) reacting a compound of formula (III) with a compound of formula (IV)using sodium cyanoborohydride (NaCNBH₃) to provide a compound of formula(II);

b) cleaving off the protecting group (PG) and the resin from thecompound of formula (II);

(c) followed by cyclisation of the cleaved compound of formula (II)using HATU and Hünig's base.

In particular embodiment, the tripeptide of formula (IV) is washed withDCM prior to adding it to the tether aldehyde or ketone of formula(III).

In a particular embodiment, the solvent of the tether aldehyde offormula (III) consists of a mixture of N-methyl-2-pyrrolidone (NMP),trimethyl orthoformate (TMOF) and acetic acid (AcOH).

In a particular embodiment, the reaction mixture is washed after theBorch reaction with DMF, DCM, MeOH/DCM and/or DMF.

In a particular embodiment, the cyclization of the deprotected andcleaved compound of formula (II) takes place using HATU and DIPEA inDMF.

In a particular embodiment, the global BOC-deprotection is achieved bytreatment with TFA in a solvent, particularly DCM, at RT.

Pharmaceutical Compositions

Another embodiment provides pharmaceutical compositions or medicamentscomprising the compounds of the invention and a therapeutically inertcarrier, diluent or pharmaceutically acceptable excipient, as well asmethods of using the compounds of the invention to prepare suchcompositions and medicaments.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may comprise componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, preservatives, solubilizers, stabilizers, wetting agents,emulsifiers, sweeteners, colorants, flavorants, salts for varying theosmotic pressure, buffers, masking agents, antioxidants, and furtheractive agents. They can also comprise still other therapeuticallyvaluable substances.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel H. C. et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems (2004) Lippincott, Williams & Wilkins,Philadelphia; Gennaro A. R. et al., Remington: The Science and Practiceof Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; andRowe R. C, Handbook of Pharmaceutical Excipients (2005) PharmaceuticalPress, Chicago. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents, diluents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.01 to 1000 mg per person of acompound of general formula (I) should be appropriate, although theabove upper limit can also be exceeded when necessary.

An example of a suitable oral dosage form is a tablet comprising about100 mg to 500 mg of the compound of the invention compounded with about30 to 90 mg anhydrous lactose, about to 40 mg sodium croscarmellose,about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment.

An example of an aerosol formulation can be prepared by dissolving thecompound, for example 10 to 100 mg, of the invention in a suitablebuffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. asalt such as sodium chloride, if desired. The solution may be filtered,e.g., using a 0.2 μm filter, to remove impurities and contaminants.

Uses

As described above, the compounds of formula (I), (I′), (Ia), (Ib) or(Ic) and their pharmaceutically acceptable salts possess valuablepharmacological properties for the treatment or prevention of infectionsand resulting diseases, particularly bacteremia, pneumonia, meningitis,urinary tract infection, and wound infection, caused by pathogens,particularly by bacteria, more particularly by Acinetobacter species,most particularly by Acinetobacter baumannii.

The compounds of formula (I), (I′), (Ia), (Ib) or (Ic) and theirpharmaceutically acceptable salts exhibit activity as antibiotics,particularly as antibiotics against Acinetobacter species, moreparticularly as antibiotics against Acinetobacter baumannii, mostparticularly as pathogen-specific antibiotics against Acinetobacterbaumannii.

The compounds of formula (I), (I′), (Ia), (Ib) or (Ic) and theirpharmaceutically acceptable salts can be used as antibiotics, i.e. asantibacterial pharmaceutical ingredients suitable in the treatment andprevention of bacterial infections, particularly in the treatment andprevention of bacterial infections caused by Acinetobacter species, moreparticularly in the treatment and prevention of bacterial infectionscaused by Acinetobacter baumannii.

The compounds of the present invention can be used, either alone or incombination with other drugs, for the treatment or prevention ofinfections and resulting diseases, particularly bacteremia, pneumonia,meningitis, urinary tract infection, and wound infection, caused bypathogens, particularly by bacteria, more particularly caused byAcinetobacter species, most particularly by Acinetobacter baumannii.

A particular embodiment of the present invention relates topharmaceutical compositions comprising compounds of formula (I), (I′),(Ia), (Ib) or (Ic) as defined above or their pharmaceutically acceptablesalts as defined above and one or more pharmaceutically acceptableexcipients.

A particular embodiment of the present invention relates topharmaceutical compositions comprising compounds of formula (I), (I′),(Ia), (Ib) or (Ic) or their pharmaceutically acceptable salts as definedabove and one or more pharmaceutically acceptable excipients for thetreatment or prevention of infections and resulting diseases,particularly bacteremia, pneumonia, meningitis, urinary tract infection,and wound infection, caused by pathogens, particularly by bacteria, moreparticularly caused by Acinetobacter species, most particularly byAcinetobacter baumannii.

A particular embodiment of the present invention relates to compounds offormula (I), (I′), (Ia), (Ib) or (Ic) or their pharmaceuticallyacceptable salts as defined above for use as therapeutically activesubstances, especially for use as therapeutically active substances forthe treatment or prevention of infections and resulting diseases,particularly bacteremia, pneumonia, meningitis, urinary tract infection,and wound infection, caused by pathogens, particularly by bacteria, moreparticularly caused by Acinetobacter species, most particularly byAcinetobacter baumannii.

A particular embodiment of the present invention relates to compounds offormula (I), (I′), (Ia), (Ib) or (Ic) or their pharmaceuticallyacceptable salts as defined above for the use in the treatment orprevention of infections and resulting diseases, particularlybacteremia, pneumonia, meningitis, urinary tract infection, and woundinfection, caused by pathogens, particularly by bacteria, moreparticularly caused by Acinetobacter species, most particularly byAcinetobacter baumannii.

A particular embodiment of the present invention relates to a method forthe treatment or prevention of infections and resulting diseases,particularly bacteremia, pneumonia, meningitis, urinary tract infection,and wound infection, caused by pathogens, particularly by bacteria, moreparticularly caused by Acinetobacter species, most particularly byAcinetobacter baumannii, which method comprises administering compoundsof formula (I), (I′), (Ia), (Ib) or (Ic) or their pharmaceuticallyacceptable salts as defined above to a subject.

A particular embodiment of the present invention relates to the use ofcompounds of formula (I), (I′), (Ia), (Ib) or (Ic) or theirpharmaceutically acceptable salts as defined above for the treatment orprevention of infections and resulting diseases, particularlybacteremia, pneumonia, meningitis, urinary tract infection, and woundinfection, caused by pathogens, particularly by bacteria, moreparticularly caused by Acinetobacter species, most particularly byAcinetobacter baumannii.

A particular embodiment of the present invention relates to the use ofcompounds of formula (I), (I′), (Ia), (Ib) or (Ic) or theirpharmaceutically acceptable salts as defined above for the preparationof medicaments for the treatment or prevention of infections andresulting diseases, particularly bacteremia, pneumonia, meningitis,urinary tract infection, and wound infection, caused by pathogens,particularly by bacteria, more particularly caused by Acinetobacterspecies, most particularly by Acinetobacter baumannii. Such medicamentscomprise compounds of formula (I), (I′), (Ia), (Ib) or (Ic) or theirpharmaceutically acceptable salts as defined above.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should however not be construed as limiting thescope of the invention.

Abbreviations Used

Agp: 2-amino-3-guanidino-propionic acid

Boc: tert. Butyloxycarbonyl

DCM: Dichlormethane

DIPEA: N,N-Diisopropylamine

DMF: N,N-Dimethylformamide

EA: Ethyl acetate

EtOAc: Ethyl acetate

EtOH: Ethanol

Fmoc: 9-Fluorenylmethoxycarbonyl

Fmoc-OSu: N-(9-Fluorenylmethoxycarbonyloxy)succinimide

HATU:O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate

HFIP: Hexafluoroisopropanol

HOBt: Hydroxy-benzotriazole

LAH: Lithium aluminium hydride

Lys: Lysine

MeCN: Acetonitrile

Mukaiyama's reagent: 2-Chloro-1-methyl-pyridinium iodide

MTBD: 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

NMP: N-Methylprolidone

Orn: Omithine

Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium(0)

THF: tetrahydrofurane

TLC: Thin layer chromatography

TMOF: Trimethyl-orthoformiate

Trp: Tryptophane

p-TSA: p-Toluenesulfonic acid or tosylic acid

HMPA: Hexamethylphosphoramide

Intermediate 1 9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To a suspension of 3-Chloro-2-fluoro-benzaldehyde (2.8 g, 16.64 mmol)and K₂CO₃ (4.5 g, 33.29 mmol) in DMF (15 mL) was added2-Mercapto-benzoic acid methyl ester (7.9 g, 49.93 mmol) and thereaction mixture was stirred for 2 h at room temperature. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (100 mL) and extracted with (3×100 mL)ethyl acetate. Combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure to get the crude compound which waspurified by silica gel column chromatography (20% ethyl acetate andhexane) to afford methyl 2-(2-chloro-6-formyl-phenyl)sulfanylbenzoate(4.4 g, 86.17%) as white solid. LC-MS: 307.2 [M+H]⁺.

To a solution of methyl 2-(2-chloro-6-formyl-phenyl)sulfanylbenzoate(4.4 g, 14.37 mmol) and tert-butyl sulphinamide (2.61 g, 21.56 mmol) inTHF (50 mL) was added titanium tetra ethoxide (4.92 g, 21.56 mmol) andthe reaction mixture was heated to 80° C. for 3 h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with water (100 mL) and extracted with ethyl acetate (3×100mL). Combined organic layers were dried over sodium sulphate andconcentrated under reduced pressure to get the crude compound which waspurified by silica gel column chromatography (20% ethyl acetate andhexane) to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-phenyl]sulfanylbenzoate(4.2 g, 71.25%) as brown solid. LC-MS: =409.8 [M+H]⁺.

To an ice cooled solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-phenyl]sulfanylbenzoate(4.2 g, 10.26 mmol) in THF (50 mL) was added LAH (1.1 g, 37.95 mmol)portion wise and the reaction mixture was stirred for 1 h at the sametemperature. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was diluted with aq. sodium sulphatesolution (50 mL) and extracted with ethyl acetate (3×100 mL). Combinedorganic layers were dried over sodium sulphate and concentrated underreduced pressure to get crude compound which was purified by trituratingwith hexane followed by pentane to getN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.7 g, 94.06%) as brown solid. LC-MS: 383.8 [M+H].

To a solution ofN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.7 g, 9.64 mmol) in DCM (100 mL) was added Dess-Martin periodinane(1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) (12.26 g, 28.90mmol) and the reaction mixture was stirred at room temperature for 4 h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with water (100 mL) and extracted with DCM(3×100 mL). Combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure to get the crude compound. The crudecompound was purified by silica gel column chromatography (ethylacetate) to getN-[[3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.7 g, 19.02%) as white solid. LC-MS: 381.8 [M+H]⁺.

To an ice cooled solution ofN-[[3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.800 g, 2.09 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (0.9mL) and the resulting reaction mixture was stirred at room temperaturefor 2 h. Progress of the reaction was monitored by TLC. Volatiles wereremoved under reduced pressure to obtain2-[2-(aminomethyl)-6-chloro-phenyl]sulfanylbenzaldehyde (0.660 g,quantitative) as off white solid. LC-MS: 278.0 [M+H]⁺.

To a solution of 2-[2-(aminomethyl)-6-chloro-phenyl]sulfanylbenzaldehyde(0.660 g, 2.09 mmol) in 5% aqueous NaHCO₃ (6 mL) was added Fmoc-OSu(0.754 g, 2.24 mmol) in CH₃CN (20 mL) and the reaction mixture wasstirred at room temperature for 3 h. Progress of the reaction mixturewas monitored by TLC. After completion, the reaction mixture was dilutedwith ethyl acetate and washed with water followed by brine. Organiclayer was dried over sodium sulfate and evaporated under reducedpressure to get the crude compound which was purified byflash-chromatography (5-7% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (0.460g, 44%) as off white solid. LC-MS: 500.3 [M+H].

¹H-NMR: (400 MHz, DMSO-d6): δ 4.22-4.19 (1H, m), 4.33-4.29 (4H, m), 6.47(1H, d, J=8.00 Hz), 7.37-7.28 (4H, m), 7.47-7.40 (3H, m), 7.57 (1H, t,J=7.8 Hz), 7.64 (1H, d, J=7.6 Hz), 7.68 (2H, d, J=7.4 Hz), 7.90-7.81(3H, m), 8.00 (1H, d, J=7.5 Hz), 10.20 (1H, s).

Intermediate 2 9H-fluoren-9-ylmethylN-[[4-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

Intermediate 2 was generated in analogy to Intermediate 1 starting fromthe accordingly substituted benzaldehyde.

¹H-NMR: (400 MHz, DMSO-d6) δ 4.20-4.22 (m; 3H); 4.32 (2H; d; J=6.8 Hz);7.6 (1H; d; J=7.6 Hz); 7.31-7.36 (m; 4H); 7.40 (3H; t; J=7.4 Hz); 7.46(1H; br s); 7.54 (2H; t; J=8.4 Hz); 7.69 (2H; d; J=7.6 Hz); 7.82-7.84(m; 1H); 7.90 (2H; d; J=7.2 Hz); 7.99 (1H; d; J=7.2 Hz); 10.21 (1H; s).

Intermediate 3 9H-fluoren-9-ylmethylN-[[5-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

Intermediate 3 was generated in analogy to Intermediate 1 starting fromthe accordingly substituted benzaldehyde.

1H-NMR: (400 MHz, DMSO-d6) δ 4.23-4.25 (m; 3H); 4.32 (2H; d; J=6.8 Hz);6.7 (1H; d; J=8.0 Hz); 7.31 (2H; t; J=7.4 Hz); 7.39-7.43 (4H; m);7.44-7.54 (2H; m); 7.70 (2H; d; J=7.6 Hz); 7.82-7.84 (m; 2H); 7.98 (2H;d; J=7.2 Hz); 10.20 (1H; s).

Intermediate 4 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanylphenyl]methyl]carbamate

Intermediate 4 was generated accordingly from commercially available[2-[2-(aminomethyl)phenyl]sulfanylphenyl]methanol.

1H NMR (600 MHz, CHCl3-d6) δ ppm 4.15-4.22 (m, 1H) 4.38 (d, J=6.9 Hz,2H) 4.48 (d, J=6.3 Hz, 2H) 5.12-5.20 (m, 1H) 6.77 (d, J=7.8 Hz, 1H)7.17-7.25 (m, 1H) 7.27-7.58 (m, 12H) 7.76 (d, J=7.6 Hz, 2H) 7.86 (d,J=7.6 Hz, 1H) 10.13-10.40 (m, 1H).

Intermediate 5 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-methoxy-phenyl]methyl]carbamate

A suspension of Na₂S.H₂O (2.43 g, 31.16 mmol) and MgSO₄ (7.79 g, 64.93mmol) in NMP (80 mL) was heated to 80° C. for 30 min under N₂atmosphere. To the resulting reaction mixture was added2-Fluoro-5-methoxy-benzaldehyde (4.0 g, 25.97 mmol) drop-wise at sametemperature and heated to 80° C. for 1 h. Then the reaction mixture wascooled to 0° C., acetic anhydride (3.42 mL, 36.36 mmol) was addeddrop-wise and stirring was continued for 1 h. The reaction mixturepartitioned between water and ethyl acetate, organic layer was separatedoff, dried over anhydrous sodium sulphate and concentrated under reducedpressure to get crude compound which was purified by flashchromatography (30% ethyl acetate in hexane) to affordS-(2-formyl-4-methoxy-phenyl) ethanethioate (2.5 g, 45%) as viscous oil.LC-MS: 210.9 (M+H).

To a stirred solution of S-(2-formyl-4-methoxy-phenyl) ethanethioate(2.5 g, 11.90 mmol) in anhydrous THF (70 mL) was added tert-butylsulphinamide (1.44 g, 11.90 mmol) followed by Titanium (IV) ethoxide(2.49 mL, 11.90 mmol). The resultant reaction mixture was heated to 60°C. for 1 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. Then the reaction mixture was poured onto water (50mL), filtered through celite and washed with ethyl acetate. Organiclayer was separated, washed with brine, dried over anhydrous sodiumsulphate and concentrated under reduced pressure to get the crudecompound which was purified by flash column chromatography (25% ethylacetate in hexane) to getS-[2-[(E)-tert-butylsulfinyliminomethyl]-4-methoxy-phenyl]ethanethioate(1.56 g, 42%) as reddish oil. LC-MS: 313.7 (M+H).

A solution ofS-[2-[(E)-tert-butylsulfinyliminomethyl]-4-methoxy-phenyl]ethanethioate(1.9 g, 6.07 mmol) in THF/EtOH (4:1; 50 mL) was degassed with argon for10 min and NaBH₄ (1.61 g, 42.5 mmol) was added portion-wise at 0° C. Thereaction mixture was stirred for 1 h. The reaction mixture was thenquenched with acetone/ethanol (1:1; degassed with argon) and stirred for1 h at room temperature. Volatiles were evaporated under reducedpressure and released under argon to affordN-[(5-methoxy-2-sulfanyl-phenyl)methyl]-2-methyl-propane-2-sulfinamide(1.65 g, crude) as yellow solid which was used as such in next stepwithout further purification. LC-MS: 273.9 (M+H).

To a solution ofN-[(5-methoxy-2-sulfanyl-phenyl)methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 2.05 mmol) in DMF (40 mL, degassed with argon prior to additionfor about 10 min) were added K₂CO₃ (1.61 g, 11.72 mmol) and2-Fluorobenzaldehyde (0.93 ml, 8.79 mmol) sequentially and the reactionmixture was stirred at 70° C. for 5 h. Then the reaction mixture wasdiluted with ethyl acetate, washed with water followed by brine, driedover sodium sulfate and concentrated under reduced pressure to get thecrude compound. The crude compound thus obtained was purified by flashcolumn chromatography (50% EtOAc in hexane) to affordN-[[2-(2-formylphenyl)sulfanyl-5-methoxy-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.64 g, 24.3% over two steps) as off-white solid. LC-MS: 378.1 (M+H).

To an ice cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-5-methoxy-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.64 g, 1.69 mmol) in dioxane (3 mL) was added 4M HCl in dioxane (10mL) and the reaction mixture was allowed to stir at room temperature for1 h. Progress of the reaction was monitored by TLC. Volatiles wereevaporated under reduced pressure to obtain2-[2-(aminomethyl)-4-methoxy-phenyl]sulfanylbenzaldehyde (0.52 g, 99%)as off-white solid. LC-MS: 274.1 (M+H).

To an ice cooled suspension of2-[2-(aminomethyl)-4-methoxy-phenyl]sulfanylbenzaldehyde (0.52 g, 1.68mmol) in acetonitrile (20 mL) and 5% aqueous NaHCO₃ solution (2 mL) wasadded Fmoc-OSu (0.57 g, 1.68 mmol) in CH₃CN (20 mL) and the reactionmixture was stirred at room temperature for 3 h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with ethyl acetate (50 mL) and organic layer was separatedoff. Organic layer was washed with water followed by brine and driedover anhydrous sodium sulfate. Organic layer was concentrated underreduced pressure to get the crude compound which was purified byflash-chromatography (10% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-methoxy-phenyl]methyl]carbamate (0.50g, 60%) as off-white solid. LC-MS: 496.4 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 3.84 (3H, s), 4.15 (1H, t, J=7.00 Hz), 4.34(2H, d, J=7.1 Hz), 4.41 (2H, d, J=6.4 Hz), 5.16 (1H, t, J=5.8 Hz), 6.65(1H, d, J=8.0 Hz), 6.90 (1H, dd, J=8.5, 2.6 Hz), 7.11 (1H, d, J=2.5 Hz),7.31-7.17 (4H, m), 7.39-7.36 (2H, m), 7.53-7.47 (3H, m), 7.74 (2H, d,J=7.5 Hz), 7.81 (1H, d, J=7.6 Hz), 10.27 (1H, s).

Intermediate 6 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate

A suspension of Na₂S. 9H₂O (4.79 g, 61.41 mmol) and MgSO₄ (10.87 g,90.31 mmol) in NMP (100 mL) was stirred at 80° C. for a period of 30 minunder argon atmosphere. To the resulting reaction mixture was added asolution of 2-Fluoro-3-methyl benzaldehyde (5 g, 36.12 mmol) in NMP (25mL) drop-wise at 80° C. and stirring was continued for 30 min at 80° C.Then the reaction mixture was cooled in an ice-bath. To the resultingreaction mixture was added acetic anhydride (6 mL) drop wise and thereaction mixture was stirred for 30 min. Progress of the reaction wasmonitored by TLC. Reaction mixture was then partitioned between waterand ethyl acetate; organic layer was separated off, dried over anhydroussodium sulfate and concentrated under reduced pressure to get the crudecompound. The crude compound was purified by flash-chromatography (25%ethyl acetate in hexane) to afford S-(2-formyl-6-methyl-phenyl)ethanethioate (3.2 g, 45.64%) as brown color solid. LC-MS: 194.25 (M+H).

To a solution of S-(2-formyl-6-methyl-phenyl) ethanethioate (3.2 g,16.47 mmol) in anhydrous THF (100 mL) were added2-methylpropane-2-sulfinamide (1.99 g, 16.47 mmol) and titanium tetraethoxide (3.76 g, 16.474 mmol) sequentially. The resultant reactionmixture was stirred for a period of 2 h under argon atmosphere at 60° C.Then the reaction mixture was cooled to ambient temperature, poured ontoice-water and filtered through a short pad of celite. Filtrate wasextracted with ethyl acetate (100 mL×2) and the combined organic layerwas washed with brine (100 mL×2), dried over anhydrous sodium sulfateand concentrated under reduced pressure to get the crude compound whichwas purified by flash-chromatography (10-20% ethyl acetate in hexane) toaffordS-[2-[(E)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]ethanethioate(2.9 g, 59.30%) as viscous oil. LC-MS: 297.44 (M+H).

A solution ofS-[2-[(E)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]ethanethioate(2.7 g, 9.091 mmol) in THF-Ethanol (4:1; 75 mL) was degassed with Argonfor 15 min and then sodium borohydride (2.75 g, 72.727 mmol) was addedportion wise at 0° C. The resulting reaction mixture was stirred for 30min at 0° C. and 30 min at room temperature. Then the reaction mixturewas quenched with acetone/ethanol (1:1; 30 mL) (degassed with argon) andstirred for 1 hour at 0° C. Volatiles were evaporated under reducedpressure and released under argon to afford2-methyl-N-[(3-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide(crude) as yellow solid. This compound was used as such in next stepwithout further purification. LC-MS: 257.41 (M+H).

To a solution of2-methyl-N-[(3-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide(2.31 g, 8.98 mmol) in DMF (80 mL) (degassed with argon prior toaddition for 10 min) were added potassium carbonate (2.48 g, 17.947mmol) and 2-Fluorobenzaldehyde (3.34 g, 26.92 mmol) and the reactionmixture was heated to 70° C. for 5 h. Then the reaction mixture wasdiluted with ethyl acetate (50 mL), washed with water (50 mL) followedby brine (50 mL×2), dried over sodium sulfate and concentrated underreduced pressure to get the crude compound. The crude compound thusobtained was purified by silica gel (100-200 mesh) column chromatography(3% methanol in DCM) to getN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.0 g, 25% over two steps) as brown color viscous oil. LC-MS: 361.53(M+H).

To an ice cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.950 g, 2.63 mmol) in dioxane (10 mL) was added 4M HCl in dioxane(0.95 mL) and the resultant reaction mixture was stirred at roomtemperature for 2 h. Progress of the reaction was monitored by TLC.Volatiles were evaporated under reduced pressure to obtain crudecompound which was washed with diethyl ether and dried to get2-[2-(aminomethyl)-6-methyl-phenyl]sulfanylbenzaldehyde (0.670 g,87.10%) as white solid. This compound was used as such in next stepwithout further purification. LC-MS: 257.36 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-6-methyl-phenyl]sulfanylbenzaldehyde (0.670 g, 2.607mmol) in 5% sodium bicarbonate (5 mL) was added a solution of Fmoc-OSU(0.879 g, 2.607 mmol) in acetonitrile (10 mL) and the reaction mixturewas stirred at room temperature for 3 h. The reaction mixture was thendiluted with ethyl acetate (50 mL) and washed with brine (50 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure toget the crude compound. The crude thus obtained was purified byflash-chromatography (25% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate (0.48 g,44.12%) as white solid. LC-MS: 479.60 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 2.29 (3H, s), 4.20 (1H, t, J=6.7 Hz), 4.26(2H, d, J=6.00 Hz), 4.30 (2H, t, J=6.8 Hz), 6.45 (1H, d, J=8.00 Hz),7.21 (1H, d, J=7.56 Hz), 7.35-7.29 (4H, m), 7.48-7.38 (4H, m), 7.69 (2H,d, J=7.52 Hz), 7.78 (1H, t, J=6.00 Hz), 7.89 (2H, d, J=7.5 Hz), 7.97(1H, d, J=6.2 Hz), 10.22 (1H, s).

Intermediate 7 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-4-methyl-phenyl]methyl]carbamate

A suspension of sodium sulfide (4.8 g, 78.04 mmol) and MgSO₄ (10.8 g,90.48 mmol) in NMP (100 mL) was stirred at 80° C. for a period of 30 minunder argon atmosphere. To the resulting reaction mixture was added asolution of 2-Fluoro-4-methyl benzaldehyde (5 g, 36.19 mmol) in NMP (25mL) drop wise at 80° C. and stirring was continued for 30 min at 80° C.Then the reaction mixture was cooled in an ice-bath. To the resultingreaction mixture was added acetic anhydride (5.1 mL, 54.29 mmol) dropwise and the reaction mixture was stirred for 30 min. Progress of thereaction was monitored by TLC. Then the reaction mixture was partitionedbetween water (150 mL) and ethyl acetate (150 mL), organic layer wasseparated off, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to get the crude compound. The crude compoundthus obtained was purified by combiflash (30% ethyl acetate in hexane)to afford S-(2-formyl-5-methyl-phenyl) ethanethioate (4.8 g, 68%) ascherry color solid. LC-MS: 195.0 (M+H).

To a solution of S-(2-formyl-5-methyl-phenyl) ethanethioate (4.8 g,24.71 mmol) in anhydrous THF (100 mL) were added2-methylpropane-2-sulfinamide (2.9 g, 24.71 mmol) followed by titaniumtetra ethoxide (5.6 g, 24.71 mmol) and the resultant reaction mixturewas stirred for a period of 30 min under argon atmosphere at 60° C. Thenthe reaction mixture was cooled to room temperature, poured ontoice-water and filtered through a short pad of celite. Filtrate wasextracted with ethyl acetate (100 mL×2), washed with brine (100 mL×2),dried over anhydrous sodium sulfate and concentrated under reducedpressure to get the crude compound which was purified by combiflash(10-20% ethyl acetate in hexane) to affordS-[2-[(E)-tert-butylsulfinyliminomethyl]-5-methyl-phenyl]ethanethioate(4.5 g, 61%) as pale orange color solid. LC-MS: 313.6 (M+H).

A solution ofS-[2-[(E)-tert-butylsulfinyliminomethyl]-5-methyl-phenyl]ethanethioate(1.5 g, 4.78 mmol) in THF-Ethanol (4:1; 40 mL) was degassed with Argonfor 15 min and then sodium borohydride (1.4 g, 38.28 mmol) was addedportion wise at 0° C. and the reaction mixture was stirred for 30 min at0° C. and 30 min at room temperature. Then the reaction mixture wasquenched with acetone/ethanol (1:1; 30 mL) (degassed with argon) andstirring continued for 1 h at 0° C. Volatiles were evaporated underreduced pressure and released under argon to afford2-methyl-N-[(4-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide asyellow solid. This compound was used as such in next step withoutfurther purification. LC-MS: 258 (M+H).

To a solution of2-methyl-N-[(4-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide (3g, crude) in DMF (60 mL) (degassed with argon prior to addition forabout 10 min) were added potassium carbonate (1.2 g, 9.32 mmol) and2-Fluorobenzaldehyde (1.7 g, 13.98 mmol) and the reaction mixture washeated to 70° C. for 5 h. Then the reaction mixture was diluted withethyl acetate (50 mL), washed with water (50 mL) followed by brine (50mL×2), dried over sodium sulfate and concentrated under reduced pressureto get the crude compound. The crude compound thus obtained was purifiedby silica gel (100-200 mesh) column chromatography (5% methanol in DCM)to getN-[[2-(2-formylphenyl)sulfanyl-4-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.6 g, 16% over two steps) as colorless liquid. LC-MS: 362.1 (M+H).

To an ice cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-4-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.8 g, 2.216 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (0.8mL) and the resultant reaction mixture was stirred at room temperaturefor 2 h. Progress of the reaction was monitored by TLC. Volatiles wereevaporated under reduced pressure to obtain crude compound which waswashed with diethyl ether and dried to get2-(2-ethyl-5-methyl-phenyl)sulfanylbenzaldehyde (0.56 g, 98%) as paleyellow solid. This compound was used as such in next step withoutfurther purification. LC-MS: 258.0 (M+H).

To a stirred suspension of2-(2-ethyl-5-methyl-phenyl)sulfanylbenzaldehyde (0.56 g, 2.17 mmol) in5% sodium bicarbonate (5 mL) was added a solution of Fmoc-OSU (0.73 g,2.18 mmol) in acetonitrile (2 mL) and the reaction mixture was stirredat room temperature for 3 h. Then the reaction mixture was diluted withethyl acetate (50 mL) and washed with brine (50 mL). Organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure to get the crude compound. The crude compound thus obtained waspurified by combiflash (30% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-4-methyl-phenyl]methyl]carbamate (0.51 g,56%) as off white solid. LC-MS: 480.5 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 2.33 (3H, s), 4.16 (1H, t, J=7.0 Hz), 4.35(2H, d, J=7.0 Hz), 4.41 (2H, d, J=6.0 Hz), 5.12 (1H, br t, J=5.3 Hz),6.75 (1H, d, J=7.7 Hz), 7.33-7.23 (5H, m), 7.42-7.35 (4H, m), 7.52 (2H,d, J=7.6 Hz), 7.74 (2H, d, J=7.5 Hz), 7.84 (1H, d, J=7.6 Hz), 10.29 (1H,s).

Intermediate 8 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]carbamate

A suspension of Na₂S.H₂O (4.79 g, 61.41 mmol) and MgSO₄ (10.87 g, 90.31mmol) in NMP (100 mL) was stirred at 80° C. for a period of 30 min underargon atmosphere. To the resulting reaction mixture was added a solutionof 2-Fluoro-5-methyl benzaldehyde (5 g, 36.12 mmol) in NMP (25 mL) dropwise at 80° C. and stirring was continued for 30 min at 80° C. Then thereaction mixture was cooled in an ice-bath gradually. To the resultingreaction mixture was added acetic anhydride (6 mL) drop wise and thereaction mixture was stirred for 30 min. Progress of the reaction wasmonitored by TLC. Then the reaction mixture was partitioned betweenwater and ethyl acetate, organic layer was separated off, dried overanhydrous sodium sulfate and concentrated under reduced pressure to getthe crude compound. The crude compound thus obtained was purified byflash-chromatography (30% ethyl acetate in hexane) to affordS-(2-formyl-4-methyl-phenyl) ethanethioate (3.3 g, 47%) as brown colorsolid. LC-MS: 194.25 (M+H).

To a stirred solution of S-(2-formyl-4-methyl-phenyl) ethanethioate (3.3g, 17.01 mmol) in anhydrous THF (100 mL) were added tert-butylsulphinamide (2.06 g, 17.01 mmol) followed by titanium tetra ethoxide(3.88 g, 17.01 mmol) and the resultant reaction mixture was stirred fora period of 2 h under argon atmosphere at 60° C. Then the reactionmixture was poured onto ice-water and filtered through a short pad ofcelite. Filtrate was extracted with ethyl acetate (100 mL×2), washedwith brine (100 mL×2), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to get the crude compound which waspurified by combiflash (10-20% ethyl acetate in hexane) to affordS-[2-[(E)-tert-butylsulfinyliminomethyl]-4-methyl-phenyl]ethanethioate(3.0 g, 59.40%) as viscous oil. LC-MS: 297.44 (M+H).

A solution of thioacetic acidS-[2-[(E)-tert-butylsulfinyliminomethyl]-4-methyl-phenyl]ethanethioate(2.0 g, 6.73 mmol) in THF-Ethanol (4:1; 75 mL) was degassed with argonfor 15 min and then sodium borohydride (2.03 g, 53.87 mmol) was addedportion wise at 0° C. and the reaction mixture was stirred for 30 min at0° C. and 30 min at room temperature. The reaction mixture was thenquenched with acetone/ethanol (1:1; 30 mL) (degassed with argon) andstirred for 1 h at 0° C. Volatiles were evaporated under reducedpressure and released under argon to afford2-methyl-N-[(5-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide(crude) as yellow solid. This compound was used as such in next stepwithout further purification. LC-MS: 257.41 (M+H).

To a solution of2-methyl-N-[(5-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide(1.73 g, 6.7 mmol) in DMF (80 mL) (degassed with argon prior to additionfor about 10 min) were added potassium carbonate (1.86 g, 13.463 mmol)and 2-fluorobenzaldehyde (2.50 g, 20.194 mmol) sequentially and thereaction mixture was heated to 70° C. for 5 h. Progress of the reactionwas monitored by TLC. Then the reaction mixture was diluted with ethylacetate (50 mL), washed with water (50 mL) followed by brine (50 mL×2),dried over sodium sulfate and concentrated under reduced pressure to getthe crude compound. The crude compound thus obtained was purified bysilica gel (100-200 mesh) chromatography (3% methanol in DCM) to getN-[[2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.840 g, 21% over two steps) as brown viscous oil. LC-MS: 361.5 (M+H).

To a solution ofN-[[2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.840 g, 3.26 mmol) in dioxane (10 mL) was added 4M HCl in dioxane(0.87 mL) and the reaction mixture was stirred at room temperature for 2h. Progress of the reaction was monitored by TLC. Volatiles wereevaporated under reduced pressure to obtain crude compound which waswashed with diethyl ether and dried to get2-(2-ethyl-4-methyl-phenyl)sulfanylbenzaldehyde (0.600 g, 88.10%) aswhite solid. This compound was used as such in next step without furtherpurification. LC-MS: 257.36 (M+H).

To a stirred suspension of2-(2-ethyl-4-methyl-phenyl)sulfanylbenzaldehyde hydrochloride (0.600 g,2.33 mmol) in 5% sodium bicarbonate (5 mL) was added Fmoc-OSU (0.787 g,2.334 mmol) in acetonitrile (10 mL) and the reaction mixture was stirredat room temperature for 3 h. Then the reaction mixture was diluted withethyl acetate (50 mL) followed by brine (50 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure to get the crudecompound. The crude compound thus obtained was purified byflash-chromatography (25% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]carbamate (0.5 g,51%) as off white solid. LC-MS: 480.1 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 2.36 (3H, s), 4.23-4.21 (3H, br m),4.30-4.28 (2H, br m), 6.64 (1H, d, J=8.0 Hz), 7.24-7.20 (2H, m),7.37-7.30 (3H, m), 7.47-7.38 (4H, m), 7.70 (2H, d, J=7.4 Hz), 7.81 (1H,t, J=5.7 Hz), 7.90 (2H, d, J=7.5 Hz), 7.95 (1H, d, J=7.6 Hz), 10.20 (1H,s).

Intermediate 9 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl]carbamate

To a solution of 2-Fluoro-3-trifluoromethyl-benzaldehyde (2.0 g, 10.41mmol) in DMF (4 mL) was added K₂CO₃ (2.8 g, 20.82 mmol) followed by2-Mercapto-benzoic acid methyl ester (2.62 g, 15.61 mmol) and thereaction mixture was stirred for 6 h at room temperature. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (30 mL) and extracted with ethyl acetate(70 mL). Organic layer was dried over sodium sulphate and concentratedunder reduced pressure to obtain methyl2-[2-formyl-6-(trifluoromethyl)phenyl]sulfanylbenzoate (3.0 g, 84.67%)as off white solid. LC-MS: 341.0 (M+H).

To a solution of methyl2-[2-formyl-6-(trifluoromethyl)phenyl]sulfanylbenzoate (3 g, 8.81 mmol)in anhydrous THF (50 mL) was added tert butylsulphinamide (1.6 g, 13.22mmol) followed by titanium (IV) ethoxide (3.49 mL, 16.6 mmol) and thereaction mixture was heated to 80° C. for 1 h under argon atmosphere.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (70 mL). Organic layer was separated off, dried over anhydroussodium sulphate and concentrated under reduced pressure to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]sulfanylbenzoate(3.8 g, 97.19%) as pale yellow viscous oil. LC-MS: 443.8 (M+H).

To an ice cooled suspension of LAH (0.977 g, 25.73 mmol) in THF (30 mL)was added methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]sulfanylbenzoate(3.8 g, 8.57 mmol) in THF (30 mL) and the reaction mixture was stirredfor 2 h at 0° C. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate solution (3 mL) and filtered through celite. Residue was washedwith ethyl acetate (80 mL) and filtrate was concentrated to getN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.6 g, 72.6%) as off white solid. LC-MS: 418.1 (M+H).

To an ice cooled solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.6 g, 6.235 mmol) in DCM (100 mL) was added Dess-Martin periodinane(7.931 g, 18.70 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was poured onto saturated sodiumbicarbonate solution and extracted with DCM (3×100 mL). Combined organiclayer was washed with sodium thiosulphate, dried over sodium sulphateand concentrated under reduced pressure to get the crude compound. Thecrude compound was purified by using combiflash (ethyl acetate) toaffordN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.2 g, 46%) as off white solid. LC-MS: 415.9 (M+H).

To an ice cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.2 g, 2.88 mmol) in dioxane (12 mL) was added 4M HCl in dioxane (1.2mL) and the reaction mixture was stirred at room temperature for 1 h.Progress of the reaction was monitored by TLC. After completion,volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-6-methyl-phenyl]sulfanylbenzaldehyde (0.88 g, 97.87%)as yellow solid. LC-MS: 311.9 (M+H).

To an ice cooled suspension of2-[2-(aminomethyl)-6-methyl-phenyl]sulfanylbenzaldehyde (0.88 g, 2.82mmol) in acetonitrile (15 mL) and 5% aqueous NaHCO₃ solution (8 mL) wasadded a solution of Fmoc-OSu (0.953 g, 2.82 mmol) in CH₃CN (15 mL) andthe reaction mixture was stirred at room temperature for 3 h. Progressof the reaction was monitored by TLC. After completion, the reactionmixture was diluted with ethyl acetate (50 mL) and organic layer wasseparated off. Organic layer was washed with water followed by brine anddried over anhydrous sodium sulfate and evaporated under reducedpressure to get the crude compound. The crude compound was purified byflash-chromatography (5-7% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate (1.1 g,82%) as white solid. LC-MS: 533.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.20 (3H, br), 4.33 (2H, d, J=6.6 Hz),6.36 (1H, d, J=7.9 Hz), 7.44-7.31 (6H, m), 7.61 (1H, d, J=7.4 Hz), 7.68(2H, d, J=7.4 Hz), 7.86-7.76 (2H, m), 7.92-7.88 (3H, m), 8.01 (1H, d,J=7.4 Hz), 10.17 (1H, s).

Intermediate 10 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-4-(trifluoromethyl)phenyl]methyl]carbamate

To a solution of 2-Fluoro-4-trifluoromethyl-benzaldehyde (2.0 g, 10.41mmol) in DMF (4 mL) was added K₂CO₃ (2.8 g, 20.82 mmol) followed by2-Mercapto-benzoic acid methyl ester (2.62 g, 15.61 mmol) and thereaction mixture was stirred for 6 h at room temperature. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (30 mL) and extracted with ethyl acetate(70 mL). Organic layer was dried over sodium sulphate and concentratedunder reduced pressure to obtain methyl2-[2-formyl-5-(trifluoromethyl)phenyl]sulfanylbenzoate (3.0 g, 84.67%)as off white solid. LC-MS: 341.1 (M+H).

To a solution of methyl2-[2-formyl-5-(trifluoromethyl)phenyl]sulfanylbenzoate (3 g, 8.81 mmol)in anhydrous THF (50 mL) was added tert butylsulphinamide (1.6 g, 13.22mmol) followed by titanium (IV) ethoxide (2.77 g, 13.22 mmol) and thereaction mixture was heated to 80° C. for 1 h under argon atmosphere.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (70 mL). Organic layer was dried over anhydrous sodium sulphateand concentrated under reduced pressure to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-5-(trifluoromethyl)phenyl]sulfanylbenzoate(3.8 g, 97.19%) as pale yellow viscous oil. LC-MS: 443.9 (M+H).

To an ice cooled suspension of LAH (0.977 g, 25.73 mmol) in THF (30 mL)was added methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-5-(trifluoromethyl)phenyl]sulfanylbenzoate(3.8 g, 8.57 mmol) in THF (30 mL) and the reaction mixture was stirredfor 2 h at OoC. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate solution (3 mL) and filtered through celite. Residue was washedwith ethyl acetate (80 mL) and filtrate was concentrated to getN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-4-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.5 g, 99%) as yellow oil. LC-MS: 418.1 (M+H).

To an ice cooled solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-4-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.5 g, 8.39 mmol) in DCM (100 mL) was added Dess-Martin periodinane(10.67 g, 25.18 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was poured onto saturated sodiumbicarbonate solution and extracted with DCM (3×100 mL). Combined organiclayer was washed with sodium thiosulphate, dried over sodium sulphateand concentrated under reduced pressure to get the crude compound. Thecrude compound was purified by using combiflash (ethyl acetate) toaffordN-[[2-(2-formylphenyl)sulfanyl-4-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 48.75%) as yellow viscous oil. LC-MS: 415.9 (M+H).

To an ice cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-4-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 4.091 mmol) in dioxane (17 mL) was added 4M HCl in dioxane (1.7mL) and the reaction mixture was stirred at room temperature for 1 h.Progress of the reaction was monitored by TLC. After completion,volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-5-(trifluoromethyl)phenyl]sulfanylbenzaldehyde (1.1g, 86%) as off white solid. LC-MS: 311.9 (M+H).

To an ice cooled suspension of2-[2-(aminomethyl)-5-(trifluoromethyl)phenyl]sulfanylbenzaldehyde (1.1g, 3.53 mmol) in acetonitrile (15 mL) and 5% aqueous NaHCO₃ solution (8mL) was added a solution of Fmoc-OSu (1.19 g, 3.53 mmol) in CH₃CN (15mL) and the reaction mixture was stirred at room temperature for 3 h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with ethyl acetate (50 mL) and organiclayer was separated off. Organic layer was washed with water followed bybrine, dried over anhydrous sodium sulfate and evaporated under reducedpressure to get the crude compound. The crude compound was purified byflash-chromatography (5-7% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-4-methyl-phenyl]methyl]carbamate (0.530g, 31%) as off white solid. LC-MS: 534.2 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.22 (1H, t, J=6.7 Hz), 4.29 (2H, d, J=5.7Hz), 4.35 (2H, d, J=6.7 Hz), 6.76 (1H, d, J=7.9 Hz), 7.35-7.31 (2H, m),7.46-7.40 (3H, m), 7.52 (1H, d, J=7.2 Hz), 7.56 (1H, d, J=7.8 Hz), 7.69(2H, d, J=7.4 Hz), 7.91-7.85 (3H, m), 7.73 (1H, s), 7.94 (1H, t, J=8.00Hz), 8.00 (1H, d, J=7.4 Hz), 10.22 (1H, s).

Intermediate 11 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]carbamate

To a solution of 2-fluoro-5-trifluoromethyl-benzaldehyde (2.0 g, 10.41mmol) in DMF (4 mL) was added K₂CO₃ (2.8 g, 20.82 mmol) followed by2-Mercapto-benzoic acid methyl ester (2.67 g, 15.61 mmol) and thereaction mixture was stirred for 4 h at room temperature. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(3×100 mL). Combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure to obtain methyl2-[2-formyl-4-(trifluoromethyl)phenyl]sulfanylbenzoate (3.5 g, 98.78%)as off white solid. LC-MS: 340.7 (M+H).

To a solution of methyl2-[2-formyl-4-(trifluoromethyl)phenyl]sulfanylbenzoate (3.5 g, 16.6mmol) in anhydrous THF (20 mL) was added tert butylsulphinamide (2.01 g,16.6 mmol) followed by titanium (IV) ethoxide (3.49 mL, 16.6 mmol) andthe reaction mixture was heated to 80° C. for 2 h under argonatmosphere. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was diluted with water (50 mL),filtered through celite and washed with ethyl acetate. Organic layer wasseparated off, washed with brine, dried over anhydrous sodium sulphateand concentrated under reduced pressure to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-(trifluoromethyl)phenyl]sulfanylbenzoate(4.0 g, 54.11%) as off white solid. LC-MS: 444.0 (M+H).

To an ice cooled suspension of LAH (1.02 g, 27.0 mmol) in THF (60 mL)was added methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-(trifluoromethyl)phenyl]sulfanylbenzoate(4.0 g, 9.02 mmol) in THF (40 mL) and the reaction mixture was stirredfor 30 min at 0° C. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate solution (5 mL) and filtered through celite. The residue waswashed with ethyl acetate (3×50 mL) and filtrate was concentrated to getN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.0 g, 79.58%) as off white solid. LC-MS: 418 (M+H).

To an ice cooled solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.0 g, 7.1 mmol) in DCM (100 mL) was added Dess-Martin periodinane (9.1g, 21.5 mmol) and the reaction mixture was stirred at room temperaturefor 1 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was poured onto saturated sodiumbicarbonate solution and extracted with DCM (3×100 mL). Combined organiclayer was washed with sodium thiosulphate, dried over sodium sulphateand concentrated under reduced pressure to get the crude compound. Thecrude compound was purified by using flash-chromatography (ethylacetate) to affordN-[[2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 56.87%) as off white solid. LC-MS: 415.7 (M+H).

To an ice cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 4.09 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (1.7mL) and the reaction mixture was stirred at room temperature for 1 h.Progress of the reaction was monitored by TLC. After completion,volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-4-(trifluoromethyl)phenyl]sulfanylbenzaldehyde (1.1g, 86.36%) as off white solid. LC-MS: 312.1 (M+H).

To a suspension of2-[2-(aminomethyl)-4-(trifluoromethyl)phenyl]sulfanylbenzaldehyde (1.0g, 3.53 mmol) in 5% aqueous NaHCO₃ solution (8 mL) was added Fmoc-OSu(1.19 g, 3.53 mmol) in CH₃CN (10 mL) and the reaction mixture wasstirred at room temperature for 3 h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith ethyl acetate (50 mL) and organic layer was separated off. Organiclayer was washed with water followed by brine, dried over anhydroussodium sulfate and evaporated under reduced pressure to get the crudecompound. The crude compound was purified by flash-chromatography (30%EtOAc in hexane) to afford 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]carbamate(0.410 g, 26.79%) as off white solid. LC-MS: 533.9 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 4.19 (1H, t, J=6.7 Hz), 4.41 (2H, d, J=6.9Hz), 4.53 (2H, d, J=6.2 Hz), 5.22 (1H, br), 6.93 (1H, d, J=7.6 Hz),7.31-7.27 (1H, m), 7.47-7.33 (6H, m), 7.56-7.51 (3H, m), 7.76-7.74 (3H,m), 7.91 (1H, d, J=8.5 Hz), 10.29 (1H, s).

Intermediate 12 9H-fluoren-9-ylmethylN-[(1S)-1-[5-chloro-2-(2-formylphenyl)sulfanyl-phenyl]ethyl]carbamate

A solution of 1-(5-chloro-2-fluorophenyl)ethan-1-one (2.0 g, 11.588mmol), (2-sulfanylphenyl)methanol (1.625 g, 11.588 mmol), 63% aq. NaOH(0.7 mL) and HMPA (5 mL) was heated to 100° C. for 5 h. Reaction mixturewas diluted with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude thus obtained was purified bynormal silica column using 20% EtOAc in hexane to get1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethanone (2.67 g,78%) as a colorless sticky liquid.

To the stirred solution of1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethanone (1.0 g,3.425 mmol) in THF (7 mL) were added (S) 2-methyl 2-propane sulfinamide(415 mg, 3.425 mmol) and Ti(OEt)₄ (3.59 ml, 17.123 mmol) and heated to70° C. for 48 h. Reaction mixture was quenched with brine solution andextracted with ethyl acetate. The separated organic layer was dried oversodium sulfate and concentrated under vacuum to affordN-[(1S)-1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]-2-methyl-propane-2-sulfinamide(1.0 g, crude) as sticky liquid.

To a stirred solution ofN-[(1S)-1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]-2-methyl-propane-2-sulfinamide(2.5 g, 6.925 mmol) in THF (30 ml) was added L-selectride (lithiumtri-sec-butyl(hydrido)borate) (10 ml) at −78° C. and stirred at the samecondition for 2 h. Then the reaction mixture was quenched with saturatedNH₄Cl solution and extracted with ethyl acetate, dried over Na₂SO₄ andconcentrated under vacuum to afford the crude which was purified bynormal silica column (30% EtOAc-Hexane) to getN-[(1S)-1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]-2-methyl-propane-2-sulfinamide(1.9 g, 68%) as off white sticky solid. MS found: 398.2 (M+H).

To a stirred solution ofN-[(1S)-1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]-2-methyl-propane-2-sulfinamide(1.0 g, 2.513 mmol) in MeOH (10 mL), was added 4M HCl/dioxane (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-[(1S)-1-aminoethyl]-4-chloro-phenyl]sulfanylphenyl]methanol (900mg, crude) as a colorless liquid. MS found: 294.1 (M+H).

To a stirred suspension of[2-[2-[(1S)-1-aminoethyl]-4-chloro-phenyl]sulfanylphenyl]methanol (900mg, 2.727 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (919.636 mg,2.727 mmol) in CH₃CN (20 mL) at 25° C. and reaction mass was stirred at25° C. for 2 h. Then reaction mass was diluted with water and extractedwith ethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure. The crude thus obtained was then purified by normal silicacolumn (20% ethyl acetate-hexane) to afford 9H-fluoren-9-ylmethylN-[(1R)-1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]carbamateas sticky solid (800 mg, 56%). MS found: 516.3 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[(1R)-1-[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]carbamate(540 mg, 1.046 mmol) in DCM/THF (1:1, 24 mL) was added MnO₂(1.819 g,20.928 mmol) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 5-20% EA/Hexane to get 9H-fluoren-9-ylmethylN-[(1S)-1-[5-chloro-2-(2-formylphenyl)sulfanyl-phenyl]ethyl]carbamate(300 mg, 55%) as a light yellow solid.

¹H-NMR: (400 MHz, DMSO-d6) δ 1.26 (3H; d; J=6.92 Hz); 4.21-4.23 (2H; m);5.08-5.12 (1H; m); 6.83 (1H; d; J=7.8 Hz); 7.31-7.33 (2H; m); 7.39-7.40(4H; m); 7.45-7.46 (m; 2H); 7.66-7.69 (3H; m); 7.90 (2H; d; J=7.4 Hz);7.96 (1H; d; J=7.4 Hz); 8.03 (1H; d; J=7.36 Hz); 10.21 (1H; s).

Intermediate 13 9H-fluoren-9-ylmethylN-[[3,6-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To an ice-cooled suspension of 3,6-Dichloro-2-fluoro-benzaldehyde (3 g,15.54 mmol) and K₂CO₃ in DMF (10 mL) was added 2-Mercapto-benzoic acidmethyl ester and the reaction mixture was stirred for 1 h at roomtemperature. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was poured onto water and extractedwith ethyl acetate (50 mL×3). Combined organic layer was washed withbrine, dried over sodium sulphate and evaporated under reduced pressureto get crude compound which was triturated with hexane to get methyl2-(3,6-dichloro-2-formyl-phenyl)sulfanylbenzoate (4.5 g, 85%) asoff-white solid.

To a stirred solution of2-(3,6-dichloro-2-formyl-phenyl)sulfanylbenzoate (4.5 g, 13.19 mmol) inanhydrous THF (100 mL) was added tert-butyl sulphinamide (2.39 g, 19.79mmol) followed by titanium (IV) ethoxide (4.51 mL, 19.79 mmol) and thereaction mixture was heated to 60° C. for 1 h under argon atmosphere.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was poured onto water (200 mL), filtered through celiteand washed with ethyl acetate (200 mL). Organic layer was separated off,washed with brine, dried over anhydrous sodium sulphate and concentratedunder reduced pressure to get the crude compound which was trituratedwith hexane to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-dichloro-phenyl]sulfanylbenzoate(5.6 g, 96%) as white solid.

To an ice-cooled suspension of LAH (1.43 g, 37.95 mmol) in THF (50 mL)was added methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-dichloro-phenyl]sulfanylbenzoate(5.6 g, 12.61 mmol) in THF (50 mL) and the reaction mixture was stirredfor 30 min. Then the reaction mixture was quenched with saturated sodiumsulphate (15 mL) solution and filtered through celite. Filtrate wasconcentrated to get crude compound which was triturated with hexane togetN-[[3,6-dichloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 96%) as an off-white solid. LC-MS: 418.0 (M+H).

To an ice-cooled solution ofN-[[3,6-dichloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(4.2 g, 10.76 mmol) in DCM (100 mL) was added Dess-Martin periodinane(6.84 g 16.14 mmol) and the reaction mixture was stirred at ambienttemperature for overnight. Then the reaction mixture was poured ontosaturated sodium bicarbonate solution and extracted with DCM (100 mL×3).Combined organic layer was washed with sodium thiosulphate solution,dried over anhydrous sodium sulphate and concentrated under reducedpressure to get the crude compound. The crude compound thus obtained waspurified by flash column chromatography (10% EtOAc in hexane) to getN-[[3,6-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 36%) as sticky solid which was used as such in next step withoutfurther purification. MS calculated: 415 MS found 416.0 (M+H).

To an ice-cooled solution ofN-[[3,6-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 3.84 mmol) in dioxane (12 mL) was added 4M HCl in dioxane (4 mL)and the reaction mixture was stirred at ambient temperature for 6 h.Volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-3,6-dichloro-phenyl]sulfanylbenzaldehyde (1.1 g, 92%)as pale yellow solid. LC-MS: 311.9 (M+H).

To an ice-cooled suspension of2-[2-(aminomethyl)-3,6-dichloro-phenyl]sulfanylbenzaldehyde (1.1 g, 3.52mmol) in acetonitrile (25 mL) was added 5% aqueous NaHCO₃ solution (10mL) followed by a solution of Fmoc-OSu (1.18 g, 3.52 mmol) in CH₃CN (15mL) and the reaction mixture was stirred at ambient temperature for 4 h.Then the reaction mixture was diluted with ethyl acetate (80 mL) andwater (50 mL). Organic layer was separated off, washed with brine anddried over anhydrous sodium sulfate. Organic layer was concentratedunder reduced pressure and the crude compound thus obtained was purifiedby flash chromatography (20% EtOAc in hexane) to obtain9H-fluoren-9-ylmethylN-[[3,6-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate(0.83 g, 44%) as white solid. LC-MS: 534.2 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 4.10 (1H, t, J=7.2 Hz), 4.26 (2H, d, J=7.1Hz), 4.80 (2H, d, J=6.0 Hz), 5.10 (1H, br), 6.53 (1H, d, J=7.6 Hz),7.31-7.27 (4H, m), 7.37 (2H, t, J=7.4 Hz), 7.52-7.46 (4H, m), 7.73 (2H,d, J=7.5 Hz), 7.84 (1H, d, J=6.2 Hz), 10.28 (1H, s).

Intermediate 14 9H-fluoren-9-ylmethylN-[[2,3-dichloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To an ice-cooled suspension of 2,3-Dichloro-6-fluoro-benzaldehyde (3 g,15.54 mmol) and K₂CO₃ (4.29 g, 31.08 mmol) in DMF (10 mL) was added2-Mercapto-benzoic acid methyl ester (2.12 mL, 15.54 mmol) and thereaction mixture was stirred for 1 h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was poured ontowater and extracted with ethyl acetate (50 mL×3). Combined organic layerwas washed with brine, dried over sodium sulphate and evaporated underreduced pressure to get crude compound which was purified by flashcolumn chromatography (10% EtOAc in hexane) to get methyl2-(3,4-dichloro-2-formyl-phenyl)sulfanylbenzoate (3 g, 57%) as anoff-white solid.

To a solution of methyl 2-(3,4-dichloro-2-formyl-phenyl)sulfanylbenzoate(3 g, 8.79 mmol) in anhydrous THF (100 mL) were added tert-butylsulphinamide (1.60 g, 13.19 mmol) and titanium (IV) ethoxide (3 mL,13.19 mmol) sequentially and the resulting reaction mixture was heatedto 60° C. for 1 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was poured ontowater (100 mL) filtered through celite and celite bed was washed withethyl acetate. Organic layer was separated off and washed with brine.Organic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure to get the crude compound which was trituratedwith hexane to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,4-dichloro-phenyl]sulfanylbenzoate(3.8 g, 92%) as an off-white solid.

To an ice-cooled suspension of LAH (0.97 g, 25.67 mmol) in THF (40 mL)was added methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,4-dichloro-phenyl]sulfanylbenzoate(3.8 g, 8.56 mmol) in THF (30 mL) and the reaction mixture was stirredfor 30 min. Then the reaction mixture was quenched with saturated sodiumsulphate (5 mL) solution, filtered through celite and celite bed waswashed with ethyl acetate (3×50 mL). Filtrate was concentrated and thecrude compound thus obtained was triturated with hexane to getN-[[2,3-dichloro-6-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.5 g, 70%) as an off-white solid. LC-MS: 417.8 (M+H).

To an ice-cooled solution ofN-[[2,3-dichloro-6-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.5 g, 5.98 mmol) in DCM (100 mL) was added Dess-Martin periodinane(3.80 g, 8.97 mmol) and the resulting reaction mixture was stirred atambient temperature for 1 h. After completion, the reaction mixture waspoured onto saturated sodium bicarbonate solution and extracted with DCM(100 mL×3). Combined organic layer was washed with sodium thiosulphatesolution and dried over anhydrous sodium sulphate.

Organic layer was concentrated under reduced pressure and the crudecompound thus obtained was purified by flash column chromatography (10%EtOAc in hexane) to getN-[[2,3-dichloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 69%) as an off-white solid. LC-MS: 416.0 (M+H).

To an ice-cooled solution ofN-[[2,3-dichloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 4.08 mmol) in dioxane (25 mL) was added 4M HCl in dioxane (10mL) and the resultant reaction mixture was allowed to stir at ambienttemperature for 6 h. Volatiles were evaporated under reduced pressure toobtain crude compound which was triturated with diethyl ether to get2-[2-(aminomethyl)-3,4-dichloro-phenyl]sulfanylbenzaldehyde (1.27 g,99%) as white solid. LC-MS: 311.9 (M+H).

To an ice-cooled suspension of2-[2-(aminomethyl)-3,4-dichloro-phenyl]sulfanylbenzaldehyde (1.3 g, 4.16mmol) in acetonitrile (40 mL) was added 5% aqueous NaHCO₃ solution (10mL) followed by a solution of Fmoc-OSu (1.40 g, 4.16 mmol) in CH₃CN (15mL) and the reaction mixture was stirred at ambient temperature for 3 h.Then the reaction mixture was diluted with ethyl acetate (100 mL) andwater (100 mL). Organic layer was separated off and washed with brine.Organic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to get the crude compound. The crude compoundthus obtained was purified by flash column chromatography (20% EtOAc inhexane) to afford 9H-fluoren-9-ylmethylN-[[2,3-dichloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate(0.610 g, 28%) as white solid. LC-MS: 534.1 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 4.17-4.15 (1H, m), 4.22-4.21 (2H, m), 4.50(2H, d, J=4.4 Hz), 6.89 (1H, d, J=7.8 Hz), 7.30 (2H, t, J=7.4 Hz),7.42-7.38 (4H, m), 7.51 (2H, t, J=7.5 Hz), 7.70-7.64 (3H, m), 7.88 (2H,d, J=7.6 Hz), 7.97 (1H, d, J=7.8 Hz), 10.19 (1H, s).

Intermediate 15 9H-fluoren-9-ylmethylN-[[2-chloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To an ice-cooled suspension of 2-chloro-6-fluoro-benzaldehyde (3 g,18.92 mmol) and K₂CO₃ in DMF (10 mL) was added 2-mercapto-benzoic acidmethyl ester (2.6 mL, 18.92 mmol) and the reaction mixture was stirredfor 1 h at room temperature. Progress of the reaction was monitored byTLC. After completion, the reaction mixture was poured onto water andextracted with ethyl acetate (3×50 mL). Combined organic layer waswashed with brine, dried over sodium sulphate and evaporated underreduced pressure to get crude compound which was purified by flashcolumn chromatography (10% EtOAc in hexane) to get methyl2-(3-chloro-2-formyl-phenyl)sulfanylbenzoate (3.4 g, 59%) as whitesolid.

To a stirred solution of methyl2-(3-chloro-2-formyl-phenyl)sulfanylbenzoate (3.4 g, 11.11 mmol) inanhydrous THF (100 mL) was added tert-butyl sulphinamide (2.01 g, 16.66mmol) followed by titanium (IV) ethoxide (3.8 mL, 16.66 mmol). Theresultant reaction mixture was heated to 60° C. for 1 h under argonatmosphere. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was poured onto water (150 mL) andfiltered through celite, washed with ethyl acetate (150 mL). Organiclayer was separated off, washed with brine, dried over anhydrous sodiumsulphate and concentrated under reduced pressure to get the crudecompound which was triturated using hexane to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-chloro-phenyl]sulfanylbenzoate(4.4 g, 97%) as an off-white solid.

To an ice-cooled slurry of LAH (1.05 g, 27.87 mmol) in THF (30 mL) wasadded methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-chloro-phenyl]sulfanylbenzoate(3.8 g, 9.29 mmol) in THF (40 mL) and the reaction mixture was stirredat room temperature for 0.5 h. Then the reaction mixture was quenchedwith saturated sodium sulphate (10 mL), filtered through celite andwashed with ethyl acetate (3×75 mL). Filtrate was concentrated to getcrude compound which was triturated with hexane to getN-[[2-chloro-6-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.2 g, 90%) as white solid. LC-MS: 384.0 (M+H).

To an ice-cooled solution ofN-[[2-chloro-6-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.2 g, 8.35 mmol) in DCM (100 mL) was added Dess-Martin periodinane(5.31 g, 12.53 mmol) and the reaction mixture was stirred at ambienttemperature for 1 h. After completion, the reaction mixture was pouredonto saturated sodium bicarbonate solution and extracted with DCM (100mL×3). Combined organic layer was washed with sodium thiosulphatesolution, dried over anhydrous sodium sulphate and concentrated underreduced pressure to get the crude compound. Crude compound was purifiedby flash column chromatography (10% EtOAc in hexane) to getN-[[2-chloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.1 g, 66%) as an off-white solid. LC-MS: 382.1 (M+H).

To an ice-cooled solution ofN-[[2-chloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.1 g, 5.51 mmol) in dioxane (30 mL) was added 4M in HCl in dioxane (10mL) and the reaction mixture was allowed to stir at room temperature for6 h. Volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-3-chloro-phenyl]sulfanylbenzaldehyde (1.5 g, 98%) aswhite solid which was used as such in next step without furtherpurification. LC-MS: 277.9 (M+H).

To an ice-cooled suspension of2-[2-(aminomethyl)-3-chloro-phenyl]sulfanylbenzaldehyde (1.5 g, 4.90mmol) in acetonitrile (40 mL) was added 5% aqueous NaHCO₃ (15 mL)followed by a solution of Fmoc-OSu (1.65 g, 4.90 mmol) in CH₃CN (10 mL)and the reaction mixture was stirred at ambient temperature for 4 h.Then the reaction mixture was diluted with ethyl acetate (100 mL) andwater (50 mL). Organic layer was separated off and washed with brine.Organic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to get the crude compound which was purified bycombiflash chromatography (20% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[2-chloro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (0.93 g,39%) as white solid. LC-MS: 499.9 (M+H).

1H-NMR: (400 MHz, DMSO-d6): δ 4.20-4.14 (3H, m), 4.47 (2H, d, J=4.4 Hz),6.86 (1H, d, J=7.9 Hz), 7.32-7.28 (2H, m), 7.43-7.36 (5H, m), 7.53-7.49(1H, m), 7.62-7.59 (2H, m), 7.68 (2H, d, J=7.4 Hz), 7.87 (2H, d, J=7.5Hz), 7.96 (1H, d, J=6.6 Hz), 10.20 (1H, s).

Intermediate 16 9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-6-(trifluoromethyl)-phenyl]methyl]carbamate

To a stirred solution of methyl 2-mercapto-benzoic acid methyl ester (2g, 11.89 mmol) and 2,3-dichloro-6-(trifluoromethyl)benzaldehyde (2.89 g,11.889 mmol) in DMF (20 mL) was added K₂CO₃ (1.64 g, 11.89 mmol) andreaction mass was stirred at 25° C. for 30 min. Reaction mixture wasdiluted with ethyl acetate and washed with water. The separated organiclayer was washed with brine solution, dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The crude thus obtainedwas purified by normal silica column using 0-5% ethyl acetate in hexaneto get methyl2-[6-chloro-2-formyl-3-(trifluoromethyl)phenyl]sulfanylbenzoate (2.3 g,51%) as a white solid. MS found: 375 (M+H).

To a stirred solution of methyl2-[6-chloro-2-formyl-3-(trifluoromethyl)phenyl]sulfanyl-benzoate (4.5 g,12.007 mmol) in THF (50 mL) was added 2-methylpropane-2-sulfinamide(1.45 g, 12.0 mmol), Ti(OEt)₄ (12.68 mL, 60.04 mmol) and reaction masswas heated to 70° C. for 16 h. The reaction mass was quenched withsaturated sodium chloride solution, solid obtained was filtered throughcelite pad, washed with ethyl acetate. The separated organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure to get ethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-3-(trifluoromethyl)phenyl]sulfanylbenzoate(5.8 g crude) which was directly used for next step without furtherpurification. MS found: 491.8 (M+H).

To a stirred solution of ethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-3-(trifluoromethyl)phenyl]sulfanylbenzoate(5.8 g, 15.185 mmol) in THF (60 mL) was added LiBH₄ (3.2 g, 151.85 mmol)and reaction mass was heated to 50° C. for 4 h. Reaction mixture wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-40% ethyl acetate in hexane to getN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-6-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.7 g, 69%, 2 steps) as a off white solid. MS found: 452.2 (M+H).

To a stirred solution ofN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-6-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.7 g, 8.18 mmol) in MeOH (40 mL), was added 4M HCl in dioxane (20 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-6-chloro-3-(trifluoromethyl)phenyl]sulfanylphenyl]methanol(3.6 g, crude) which was directly used for next step without furtherpurification. MS found: 347.8 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-3-(trifluoromethyl)phenyl]sulfanylphenyl]methanol(3.6 g, 9.368 mmol) in 5% NaHCO₃(35 mL) was added Fmoc OSU (3.1 g, 9.368mmol) in CH₃CN (35 mL) at 25° C. and reaction mixture was stirred at 25°C. for 2 h. Then reaction mass was diluted with water and extracted withethyl acetate. The separated organic layer was washed with brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-30% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-6-(trifluoromethyl)phenyl]methyl]carbamate(2.96 g, 63%, 2 steps) as a off white solid. MS found: 569.9 (M+H).

To a stirred solution of get 9H-fluoren-9-ylmethylN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-6-(trifluoromethyl)phenyl]methyl]carbamate(2.9 g, 5.087 mmol) in DCM/THF (1:1, 60 mL) was added MnO₂(8.84 g,101.749 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-6-(trifluoromethyl)phenyl]methyl]carbamate(2 g, 69%) as a off white solid. MS found: 567.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6) δ 4.01-4.03 (1H; m); 4.22-4.28 (2H; m); 4.41(2H; d; J=5.6 Hz); 6.53 (1H; d; J=7.76 Hz); 7.30 (2H; t; J=7.4 Hz); 7.42(3H; t; J=7.4 Hz); 7.49-7.51 (1H; m); 7.67 (2H; d; J=7.36 Hz); 7.74 (1H;br s); 7.89 (2H; d; J=7.8 Hz); 7.99-8.03 (2H; m); 8.07 (1H; s); 10.20(1H; s).

Intermediate 17 9H-fluoren-9-ylmethylN-[[3,6-difluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To a stirred solution of methyl 2-Mercapto-benzoic acid methyl ester(1.37 g, 8.153 mmol) and 2-chloro-3,6-difluorobenzaldehyde (1.43 g,8.153 mmol) in DMF (12 mL) was added K₂CO₃(1.12 g, 8.153 mmol) andreaction mass was stirred at 25° C. for 30 min. Reaction mixture wasdiluted with ethyl acetate and washed with water. The separated organiclayer was washed with brine solution, dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The crude thus obtainedwas purified by normal silica column using 0-2% ethyl acetate in hexaneto get methyl 2-(3,6-difluoro-2-formyl-phenyl)sulfanylbenzoate (1 g,40%) as a yellow solid. MS found: 309.3 (M+H).

To a stirred solution of methyl2-(3,6-difluoro-2-formyl-phenyl)sulfanylbenzoate (1.7 g, 5.519 mmol) inTHF (20 mL) was added 2-methylpropane-2-sulfinamide (0.669 g, 5.519mmol), Ti(OEt)₄(5.786 mL, 27.597 mmol) and reaction mass was heated to70° C. for 4 h. The reaction mass was quenched with saturated sodiumchloride solution, solid obtained was filtered through celite pad,washed with ethyl acetate. The separated organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure to getethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-difluoro-phenyl]sulfanylbenzoate(2.4 g crude) which was directly used for next step without furtherpurification. MS found: 425.7 (M+H).

To a stirred solution of ethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-difluoro-phenyl]sulfanylbenzoate(2.4 g, 5.647 mmol) in THF (30 mL) was added LiBH₄ (1.23 g, 56.471 mmol)and reaction mass was heated to 70° C. for 2 h. Reaction mixture wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-50% ethyl acetate in hexane to getN-[[3,6-difluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 75%, 2 steps) as a off white solid. MS found: 385.9 (M+H).

To a stirred solution ofN-[[3,6-difluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 3.855 mmol) in MeOH (25 mL), was added 4M HCl in dioxane (12 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-3,6-difluoro-phenyl]sulfanylphenyl]methanol (1.6 g,crude) which was directly used for next step without furtherpurification. MS found: 281.9 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-3,6-difluoro-phenyl]sulfanylphenyl]methanol (1.6 g,5.112 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (1.724 g, 5.112 mmol)in CH₃CN (20 mL) at 25° C. and reaction mixture was stirred at 25° C.for 3 h. Then reaction mass was diluted with water and extracted withethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure. The crude thus obtained was purified by normal silica columnusing 30% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[3,6-difluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(2 g, 95%, 2 steps) as a off white solid. MS found: 503.9 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3,6-difluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(2 g, 3.976 mmol) in DCM/THF (1:1, 50 mL) was added MnO₂ (6.913 g,79.523 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 0-12% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3,6-difluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (1g, 50%) as a off white solid. MS found: 502.1 (M+H).

¹H-NMR: (400 MHz, DMSO-d6) δ 4.12-4.14 (3H; m); 4.40 (2H; d; J=3.68 Hz);6.70 (1H; d; J=7.76 Hz); 7.20-7.31 (2H; m); 7.33-7.45 (4H; m); 7.49-7.53(1H; m); 7.64 (2H; d; J=7.44 Hz); 7.69 (1H; m); 7.82 (2H; d; J=7.52 Hz);7.99 (1H; d; J=7.4 Hz); 10.19 (1H; s).

Intermediate 18 9H-fluoren-9-ylmethylN-[[2-(2-fluoro-6-formyl-phenyl)sulfanylphenyl]methyl]carbamate

To an ice cooled suspension of 2,3-Difluoro-benzaldehyde (4.0 g, 28.16mmol) and K₂CO₃ (7.77 g, 56.33 mmol) in DMF (15 mL) was added2-Mercapto-benzoic acid methyl ester (4.7 g, 28.16 mmol) and thereaction mixture was stirred for 1 h at 0° C. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture was dilutedwith water (100 mL) and extracted with ethyl acetate (2×100 mL).Combined organic layers were dried over sodium sulphate and concentratedunder reduced pressure to get crude compound which was triturated withhexane to get methyl 2-(2-fluoro-6-formyl-phenyl)sulfanylbenzoate (5.5g, 67%) as off-white solid. LCMS: 290.9 (M+H).

To a solution of methyl 2-(2-fluoro-6-formyl-phenyl)sulfanylbenzoate(i.e. 3 d) (3 g, 10.34 mmol) in toluene (50 mL) were added ethyleneglycol (1.2 mL, 20.68 mmol) and p-TSA (0.19 g, 1.03 mmol) and thereaction mixture was heated to 140° C. using Dean-Stark condenser for 3h. Progress of the reaction was monitored by TLC. Then the reactionmixture was poured onto saturated sodium bicarbonate solution andextracted with ethyl acetate (2×50 mL). Combined organic layer was driedover anhydrous sodium sulfate, filtered and concentrated to get methyl2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylbenzoate (3 g, 86%)which was used as such in next step without purification. LC-MS: 334.7(M+H).

To an ice cooled suspension of LAH (1.19 g, 31.43 mmol) in THF (40 mL)was added a solution of get methyl2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylbenzoate (3.5 g, 10.47mmol) in THF (40 mL) and the reaction mixture was stirred for 30 min.Then the reaction mixture was quenched with saturated sodium sulphatesolution (20 mL), stirred for 30 min and filtered through celite, washedwith ethyl acetate (3×100 mL). Filtrate was concentrated to get[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methanol (3 g,93%) as viscous oil. LC-MS: 324 (M+NH₄).

To an ice cooled solution of[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methanol (3 g,9.80 mmol) in DCM (50 mL) were added Et₃N (4.08 mL, 29.41 mmol) andmethanesulfonyl chloride (1.13 g, 14.70 mmol) and the resultant reactionmixture was stirred for 30 min. Then the reaction mixture was diluted bywater (100 mL) and extracted with DCM (50 mL). Organic layer was driedover anhydrous sodium sulphate and concentrated under reduced pressureto afford[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methylmethanesulfonate (3.5 g, 93%) as pale yellow liquid which was used assuch in next step without further purification. LC-MS: 384.9 (M+H).

To a solution of[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methylmethanesulfonate (3.5 g, 9.11 mmol) in THF (40 mL) was added liquidammonia (15 mL) at −78° C. Then the reaction mixture gradually heated to55° C. for 4 h. Volatiles were removed under reduced pressure to afford[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methanamine(2.5 g, 94%) as viscous oil. LCMS: 305.8 (M+H).

To an ice cooled suspension of[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methanamine(2.5 g, 8.19 mmol) in acetonitrile (60 mL) was added 5% aqueous NaHCO₃(5 mL) followed by a solution of Fmoc-OSu (2.76 g, 8.19 mmol) in CH₃CN(40 mL) and the reaction mixture was stirred at ambient temperature for4 h. It was then diluted with ethyl acetate (200 mL) and water (200 mL).Organic layer was separated off, washed with water, brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure to getthe crude compound. The crude compound thus obtained was purified byflash-chromatography (20% EtOAc in hexane) to get 9H-fluoren-9-ylmethylN-[[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methyl]carbamate(1.5 g, 39%) as white solid. LC-MS: 527.6 (M+H).

To an ice cooled solution of 9H-fluoren-9-ylmethylN-[[2-[2-(1,3-dioxolan-2-yl)-6-fluoro-phenyl]sulfanylphenyl]methyl]carbamate(1.5 g, 2.84 mmol) in acetone (50 mL) was added of conc. HCl solution (8mL) and the reaction mixture was stirred at RT for 1 h. Progress of thereaction was monitored by TLC. After completion, volatiles were removedunder reduced pressure and the crude reaction mixture was dissolved insodium bicarbonate solution. The aq. layer was extracted with ethylacetate, dried over anhydrous sodium sulphate, filtered and concentratedto get crude compound which was further purified by flash columnchromatography (20% EtOAc in hexane) to get 9H-fluoren-9-ylmethylN-[[2-(2-fluoro-6-formyl-phenyl)sulfanylphenyl]methyl]carbamate (1.0 g,72%) as white solid. LC-MS: 483.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.26-4.23 (1H, m), 4.38-4.35 (4H, m), 6.86(1H, d, J=7.7 Hz), 7.19-7.14 (1H, m), 7.23-7.22 (2H, m), 7.33 (2H, t,J=7.3 Hz), 7.42 (2H, t, J=7.3 Hz), 7.79-7.64 (5H, m), 7.93-7.88 (3H, m),10.44 (1H, s).

Intermediate 19 9H-fluoren-9-ylmethylN-[[3-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To an ice cooled suspension of 2,3-Difluoro-benzaldehyde (4.7 g, 28.16mmol) and K₂CO₃ (7.77 g, 56.33 mmol) in DMF (15 mL) was added2-Mercapto-benzoic acid methyl ester (4 g, 28.16 mmol) and the reactionmixture was stirred for 1 h at 0° C. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith water (100 mL) and extracted with ethyl acetate (2×100 mL).Combined organic layers were dried over sodium sulphate and concentratedunder reduced pressure to get crude compound which was triturated withhexane to get methyl 2-(2-fluoro-6-formyl-phenyl)sulfanylbenzoate (5.5g, 67%) as off-white solid. LCMS: 290.9 (M+H).

To a solution of methyl 2-(2-fluoro-6-formyl-phenyl)sulfanylbenzoate (3g, 10.34 mmol) in dry THF (50 mL) under argon atmosphere at roomtemperature was added tert-butyl sulphinamide (1.87 g, 15.51 mmol)followed by titanium (IV) ethoxide (3.53 g, 15.51 mmol) and the reactionmixture was heated to 70° C. for 3 h. After completion, the reactionmixture was cooled to room temperature, poured onto water (10 mL) andfiltered through celite bed. Celite bed was washed with ethyl acetate(100 mL). Organic layer was separated off, washed with water (100 mL)and dried over anhydrous sodium sulfate. Organic layer was concentratedunder reduced pressure to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-fluoro-phenyl]sulfanylbenzoate(2.5 g, 61%) as yellow solid. LCMS: 393.8 (M+H).

To an ice cooled suspension of LAH (0.72 g, 19.04 mmol) in THF (30 mL)was methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-fluoro-phenyl]sulfanylbenzoate(2.5 g, 6.36 mmol) in THF (40 mL) and the reaction mixture was stirredat that temperature for 30 min. Then the reaction mixture was quenchedwith saturated sodium sulphate solution (15 mL) and filtered throughcelite. Filtrate was concentrated to getN-[[3-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.2 g, 94%) as off-white solid. LCMS: 367.8 (M+H).

To an ice cooled solution ofN-[[3-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.2 g, 5.99 mmol) in DCM (100 mL) was added Dess-Martin periodinane(3.81 g, 8.99 mmol) and the reaction mixture was stirred at RT for 1 h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with NaHCO₃ (100 mL) and extracted with DCM(2×100 mL). Combined organic layer was washed with saturated sodiumthiosulphate solution, dried over anhydrous sodium sulphate, filteredand concentrated to get crude compound which was purified by flashcolumn chromatography (50% EtOAc in hexane) to getN-[[3-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g, 82%) as white solid. LCMS: 365.8 (M+H).

To an ice cooled solution ofN-[[3-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g, 2.88 mmol) in dioxane (40 mL) was added HCl in dioxane (20 mL,4M) and the reaction mixture was stirred at RT for 3 h. Progress of thereaction was monitored by TLC. Volatiles were removed under reducedpressure and the crude compound was triturated with diethyl etherfollowed by drying under reduced pressure to get2-[2-(aminomethyl)-6-fluoro-phenyl]sulfanylbenzaldehyde (1 g, 88%) aswhite solid. LCMS: 261.7 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-6-fluoro-phenyl]sulfanylbenzaldehyde (1.0 g, 3.83mmol) in acetonitrile (50 mL) and 5% aqueous was added a solution ofFmoc-OSu (1.29 g, 3.83 mmol) in acetonitrile (30 mL) and the reactionmixture was stirred at ambient temperature for 4 h. It was then dilutedwith ethyl acetate (200 mL) and water (200 mL). Organic layer wasseparated off, washed with water, brine, dried over anhydrous sodiumsulfate and evaporated under reduced pressure to get crude compound. Thecrude compound thus obtained was purified by flash-chromatography (10%ethyl acetate in hexane) to afford 9H-fluoren-9-ylmethylN-[[3-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (0.65 g,22% over two steps) as white solid. LCMS: 484.0 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.21 (1H, t, J=6.6 Hz), 4.33-4.28 (4H, m),6.60 (1H, d, J=8.0), 7.23 (1H, d, J=7.7 Hz), 7.48-7.30 (7H, m),7.64-7.58 (1H, m), 7.68 (2H, d, J=7.4 Hz), 7.90-7.85 (3H, m), 8.00 (1H,d, J=6.9 Hz), 10.19 (1H, s).

Intermediate 20 9H-fluoren-9-ylmethylN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl] carbamate

To a suspension of 5-Chloro-2-fluoro-3-trifluoromethyl-benzaldehyde (1.5g, 6.62 mmol) and K₂CO₃ (1.8 g, 13.24 mmol) in DMF (15 mL) was added2-Mercapto-benzoic acid methyl ester (1.1 g, 6.62 mmol) added and thereaction mixture was stirred for 2 h at room temperature. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (100 mL) and extracted with (3×250 mL)ethyl acetate. Combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure to get crude compound which waspurified by silica gel (100-200 mesh) column chromatography (20% ethylacetate and hexane) to get methyl2-[4-chloro-2-formyl-6-(trifluoromethyl)phenyl]sulfanylbenzoate (2.3 g,93%) as brown solid.

To a solution of methyl2-[4-chloro-2-formyl-6-(trifluoromethyl)phenyl]sulfanylbenzoate (2.6 g,6.95 mmol) and tert-butyl sulphinamide (1.8 g, 15.29 mmol) in THF (50mL) was added titanium tetraethoxide (3.48 g, 15.29 mmol) and thereaction mixture was heated to 60° C. for 3 h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture was dilutedwith water (100 mL) and extracted with ethyl acetate (3×100 mL).Combined organic layer was dried over sodium sulphate and concentratedto get crude compound which was purified by silica gel (100-200 mesh)column chromatography (30% ethyl acetate and hexane) to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-chloro-6-(trifluoromethyl)phenyl]sulfanylbenzoate(1.9 g, 57%) as brown solid. LC-MS: 477.9 (M+H).

To an ice cooled suspension LAH (0.45 g, 11.95 mmol) in THF (20 mL) wasadded a solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-chloro-6-(trifluoromethyl)phenyl]sulfanylbenzoate(1.9 g, 3.98 mmol) in THF (30 mL) and the reaction mixture was stirredfor 1 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with aq. sodium sulphatesolution (50 mL) and extracted with ethyl acetate (3×100 mL). Combinedorganic layer was dried over sodium sulphate and concentrated underreduced pressure to get crude compound which was washed with hexanefollowed by pentane to getN-[[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 89%) as off white solid. LC-MS: 452.0 (M+H).

To a suspension ofN-[[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 3.54 mmol) in DCM (50 mL) was added Dess-Martin periodinane (3.7g, 8.86 mmol) and the reaction mixture was stirred at RT for 2 h.Progress the reaction mass was monitored by TLC. After completion, thereaction mixture was diluted with water (100 mL) and extracted with DCM(3×100 mL). Combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure to get crude compound. The crudecompound thus obtained was purified by silica gel (100-200 mesh) columnchromatography (ethyl acetate) and concentrated under reduced pressureto getN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.900 g, 56%) as white solid. LC-MS: 449.7 (M+H).

To an ice cooled solution ofN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.9 g, 0.0020 mol) in 1,4 dioxane (20 mL) was added 4M HCl in dioxane(4 mL) and the reaction mixture was stirred at ambient temperature for 2h. Volatiles were removed under reduced pressure to obtain2-[2-(aminomethyl)-4-chloro-6-(trifluoromethyl)phenyl]sulfanylbenzaldehyde(0.65 g, 94%) as off white solid. LC-MS: 346.0 (M+H).

To a solution ofN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.9 g, 0.0020 mol) in 5% aqueous NaHCO₃ solution (12 mL) was addedFmoc-OSu (0.558 g, 0.0020 mol) in CH₃CN (50 mL) and the reaction mixturewas stirred at room temperature for 3 h. Then the reaction mixture wasdiluted with ethyl acetate and washed with water followed by brine.Organic layer was separated off, dried over sodium sulfate andevaporated under reduced pressure to get the crude compound which waspurified by flash-chromatography to get 9H-fluoren-9-ylmethylN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-(trifluoromethyl)phenyl]methyl]carbamate(0.435 g, 32%) as off white solid. LC-MS: 568.0 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.23-4.20 (3H, m), 4.32-4.30 (2H, m), 6.43(1H, d, J=8.0 Hz), 7.34-7.30 (2H, m), 7.44-7.37 (4H, m), 7.67 (2H, d,J=7.4 Hz), 7.70 (1H, br s), 7.89 (3H, d, J=7.5 Hz), 8.03-8.00 (2H, m),10.15 (1H, s).

Intermediate 21 9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]carbamate

A suspension of 3-Chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (2.5 g,11.06 mmol) and K₂CO₃ (3.0 g, 22.12 mmol) in DMF (15 mL) was added2-Mercapto-benzoic acid methyl ester (1.8 g, 11.06 mmol) and thereaction mixture was stirred for 2 h at room temperature. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(3×250 mL). Combined organic layer was dried over sodium sulphate andconcentrated under reduced pressure to get crude compound. The crudecompound thus obtained was purified by silica gel column chromatography(100-200 mesh) using 20% ethyl acetate and hexane as eluent to getmethyl 2-[2-chloro-6-formyl-4-(trifluoromethyl)phenyl]sulfanylbenzoate(3.5 g, 85%) as brown solid.

To a suspension of methyl2-[2-chloro-6-formyl-4-(trifluoromethyl)phenyl]sulfanylbenzoate (3.5 g,9.36 mmol) and tert-butyl sulphinamide (1.6 g, 14.03 mmol) in THF (50mL) was added titanium tetraethoxide (3.2 g, 14.03 mmol) and thereaction mixture was heated to 60° C. for 3 h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture was dilutedwater (100 mL) and extracted with ethyl acetate (3×100 mL). Combinedorganic layer was dried over sodium sulphate and concentrated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by silica gel (100-200 mesh) column chromatography (30%ethyl acetate and hexane) to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-4-(trifluoromethyl)phenyl]sulfanylbenzoate(4 g, 89%) as brown solid. LC-MS: 477.9 (M+H).

To an ice cooled suspension of LAH (0.955 g, 25.15 mmol) in THF (25 mL)was added a solution of2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-4-(trifluoromethyl)phenyl]sulfanylbenzoate(4 g, 8.38 mmol) in THF (25 mL) and the reaction mixture was stirred for1 h. Progress of the reaction was monitored by TLC. After completion,the reaction mixture was diluted with aq. sodium sulphate solution (100mL) and extracted with ethyl acetate (3×250 ml). Combined organic layerwas dried over sodium sulphate and concentrated under reduced pressureto get crude compound which was purified by washing with hexane followedby pentane to getN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.9 g, 95%) as brown solid. LC-MS: 452.1 (M+H).

To a solution ofN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.9 g, 8.64 mmol) in DCM (100 mL) was added Dess-Martin periodinane(9.17 g, 21.62 mmol) and the reaction mixture was stirred at RT for 3 h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with NaHCO₃ solution (100 mL) and extractedwith DCM (3×100 mL). Combined organic layer was dried over sodiumsulphate and concentrated under reduced pressure to get crude compound.The crude compound thus obtained was purified by silica gel (100-200mesh) column chromatography (ethyl acetate) to getN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g, 51%) as white solid. LC-MS: 449.7 (M+H).

To an ice cooled solution ofN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g, 4.45 mmol) in 1,4 dioxane (50 mL) was added 4M HCl in dioxane (4mL) and the resultant reaction mixture was stirred at ambienttemperature for 2 h. Volatiles were evaporated under reduced pressure toobtain2-[2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl]sulfanylbenzaldehyde(1.5 g, 98%) as off white solid. LC-MS: 346.1 (M+H).

To a solution of2-[2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl]sulfanylbenzaldehyde(2 g, 5.24 mmol) in 5% aqueous NaHCO₃ solution (12 mL) was addedFmoc-OSu (1.42 g, 4.19 mmol) in CH₃CN (50 mL) and the reaction mixturewas stirred at ambient temperature for 3 h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith ethyl acetate and washed with water followed by brine. Combinedorganic layer was dried over sodium sulfate and evaporated under reducedpressure to get crude compound which was purified byflash-chromatography to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-(trifluoromethyl)phenyl]methyl]carbamate(0.700 g, 34%) as off white solid. LC-MS: 568.1 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 4.15 (1H, t, J=6.9 Hz), 4.37 (2H, d, J=6.9Hz), 4.55 (2H, d, J=6.4 Hz), 5.29-5.26 (1H, br), 6.52 (1H, d, J=7.0 Hz),7.29-7.27 (2H, m), 7.34-7.30 (2H, m), 7.41-7.36 (2H, m), 7.51 (2H, d,J=7.4 Hz), 7.76-7.73 (4H, m), 7.87-7.85 (1H, m), 10.25 (1H, s).

Intermediate 22 9H-fluoren-9-ylmethylN-[[3-chloro-6-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To a solution of 2,3 dichloro 6-fluoro benzaldehyde (1.0 g, 5.208 mmol)in DMF (7.0 ml) were added K₂CO₃ (720 mg, 5.208 mmol) and methyl2-sulfanylbenzoate (876 mg, 5.208 mmol) and stirred at 25° C. for 30min. Reaction mixture was diluted with water and extracted with EtOAc.The combined organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to get the compound whichwas purified by normal silica column using 0-2% ethyl acetate in hexaneto get methyl 2-(6-chloro-3-fluoro-2-formyl-phenyl)sulfanylbenzoate (354mg, 21%) as a yellow solid.

To the stirred solution of methyl2-(6-chloro-3-fluoro-2-formyl-phenyl)sulfanylbenzoate (1.7 g, 5.247mmol) in THF (25 mL) were added 2-methyl 2-propane sulfinamide (0.636 g,5.247 mmol) and Ti(OEt)₄ (5.5 mL, 26.235 mmol) and reaction mixture washeated to 70° C. for 4 h. Reaction mixture was quenched with brinesolution and extracted with ethyl acetate, dried over sodium sulphateand concentrated under vacuum to afford ethyl2-({6-chloro-3-fluoro-2-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)benzoate(2.2 g, crude) as a yellow liquid. MW found: 442.3 (M+H).

To a stirred solution of ethyl2-({6-chloro-3-fluoro-2-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)benzoate(2.4 g, 5.442 mmol) in THF (25 mL) was added LiBH₄ (1.185 g, 54.422mmol) at 0° C. and reaction mass was heated to 70° C. for 4 h. Thesolvent was evaporated and the reaction mixture was quenched with NH₄Cland extracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 0-50% ethyl acetate in hexane to getN-[[3-chloro-6-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 64%) as a off-white solid. MS found: 402.2 (M+H).

To a stirred solution ofN-[[3-chloro-6-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 3.373 mmol) in MeOH (25 mL), was added 4M HCl in dioxane (12 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-6-chloro-3-fluoro-phenyl]sulfanylphenyl]methanol(1.4 g, crude) as a white solid. MS found: 298.2 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-3-fluoro-phenyl]sulfanylphenyl]methanol(1.4 g, 4.714 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (1.589 g,4.714 mmol) in CH₃CN (20 mL) at 25° C. and reaction mixture was stirredat 25° C. for 3 h. Then reaction mixture was diluted with water andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-50% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[3-chloro-6-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(1.6 g, 88%, 2 steps) as off-white solid. MS found: 520 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-6-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(1.6 g, 3.083 mmol) in DCM/THF (1:1, 50 mL) was added MnO₂(5.36 g,61.657 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 0-13% ethyl acetate in hexane to afford9H-fluoren-9-ylmethylN-[[3-chloro-6-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate(1.0 g, 63%) as a off-white solid. MS found: 517.8 (M+H).

¹H-NMR: (400 MHz, DMSO-d6) δ 4.12-4.14 (3H; m); 4.40 (2H; br s); 6.55(1H; d; J=7.92 Hz); 7.28-7.31 (2H; m); 7.33-7.45 (4H; m); 7.51 (1H; t;J=8.96 Hz); 7.62 (2H; d; J=7.44 Hz); 7.70-7.72 (1H; m); 7.82 (2H; d;J=7.52 Hz); 7.99 (1H; d; J=7.4 Hz); 10.19 (1H; s).

Intermediate 23 9H-fluoren-9-ylmethylN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-3-(trifluoromethyl)phenyl]methyl]carbamate

To an ice-cooled solution of 2-Fluoro-3-trifluoromethyl-benzaldehyde(3.2 g, 20.87 mmol) in DMF (30 mL) was added sodium hydride portion-wise(1.663 g, 9.16 mmol) and the reaction mixture was stirred for 30 min. Tothe resulting reaction mixture was added a solution of2-Mercapto-nicotinic acid methyl ester (2.2 g, 13.87 mmol) in DMF (10mL) dropwise and the reaction mixture was heated to 90° C. for 9 h.Progress of the reaction was monitored by TLC.

After completion, the reaction mixture was cooled at 0° C. and potassiumcarbonate (3.83 g, 27.742 mmol) followed by methyl iodide (5.90 g, 27.74mmol) were added. The reaction mixture was stirred at room temperaturefor 16 h. After completion, the reaction mixture was diluted with icecold water (100 mL) and extracted with (3×100 mL) ethyl acetate.Combined organic layer was dried over sodium sulphate and concentratedunder reduced pressure to obtain crude compound. The crude compound waspurified by flash-chromatography (30% EtOAc in hexane) to afford methyl2-[2-formyl-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.3 g, 33%) as an off-white solid. LC-MS: 341.7 (M+H).

To a solution of afford methyl2-[2-formyl-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.3 g, 3.81 mmol) in anhydrous THF (50 mL) was added tertbutylsulphinamide (2.31 g, 19.06 mmol) followed by titanium (IV)ethoxide (4.34 g, 19.06 mmol) and the reaction mixture was heated to 60°C. for 2 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith water (50 mL), filtered through celite and washed with ethylacetate. Organic layer was separated off, washed with brine, dried overanhydrous sodium sulphate and concentrated under reduced pressure to getcrude compound which was purified by flash-chromatography (30% EtOAc inhexane) to afford methyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.3 g, 77%) as an off-white solid. LC-MS: 444.9 (M+H).

To an ice-cooled suspension of LAH (0.277 g, 7.32 mmol) in THF (50 mL)was added2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.3 g, 2.93 mmol) in THF (30 mL) and the reaction mixture was stirredfor 30 min at 0° C. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate (5 mL) and filtered through celite. The residue was washed withethyl acetate (3×50 mL) and the filtrate was concentrated to getN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-(trifluoromethyl)phenyl]methylene]-2-methyl-propane-2-sulfinamide(1.1 g, 90%) as sticky mass. LC-MS: 418.7 (M+H).

To an ice-cooled solution ofN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-(trifluoromethyl)phenyl]methylene]-2-methyl-propane-2-sulfinamide(1.1 g, 2.63 mmol) in DCM (100 mL) was added Dess-Martin periodinane(1.45 g, 3.421 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was poured onto saturated sodiumbicarbonate solution and extracted with DCM (3×100 mL). Combined organiclayer was washed with sodium thiosulphate, dried over sodium sulphateand concentrated under reduced pressure to get the crude compound. Thecrude compound was purified by flash-chromatography (30% EtOAc inhexane) to affordN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.750 g, 69%) as an off-white solid. LC-MS: 416.9 (M+H).

To an ice-cooled solution ofN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.750 g, 1.80 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (1.0mL) and the reaction mixture was stirred at room temperature for 1 h.Progress of the reaction was monitored by TLC. After completion,volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carbaldehyde(0.620 g, 100%) as an off-white solid. LC-MS: 313.0 (M+H).

To a suspension of2-[2-(aminomethyl)-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carbaldehyde(0.620 g, 1.9808 mmol) in 5% aqueous NaHCO₃ solution (5 mL) was addedFmoc-OSu (0.534 g, 1.5846 mmol) in CH₃CN (10 mL) and the reactionmixture was stirred at room temperature for 4 h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with ethyl acetate (50 mL) and organic layer was separatedoff. Organic layer was washed with water followed by brine and driedover anhydrous sodium sulfate and evaporated under reduced pressure toget the crude compound. The crude compound was purified byflash-chromatography (30% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-3-(trifluoromethyl)phenyl]methyl]carbamate(0.635 g, 60%) as white solid. LC-MS: 534.8 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.21 (3H, m), 4.34 (2H, d, J=8.8 Hz),7.44-7.29 (5H, m), 7.58 (1H, d, J=7.6 Hz), 7.72-7.67 (3H, m), 7.83-7.81(2H, m), 7.89 (2H, d, J=7.5 Hz), 8.40-8.36 (2H, m), 10.18 (1H, s).

Intermediate 24 9H-fluoren-9-ylmethylN-[[5-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To an ice-cooled solution of 5-Chloro-2-fluoro-benzaldehyde (5.14 g,33.10 mmol) in DMF (80 mL) was added sodium hydride portion-wise (1.52g, 66.20 mmol) and the reaction mixture was stirred for 30 min. To theresulting reaction mixture was added 2-Mercapto-nicotinic acid methylester (3.5 g, 22.06 mmol) in DMF (20 mL) and the reaction mixture washeated at 90° C. for 9 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was cooled at 0° C. and potassiumcarbonate (6.1 g, 44.14 mmol) and methyl iodide (9.39 g, 66.20 mmol)were added. Then the reaction mixture was stirred at room temperaturefor 16 h. After completion, the reaction mixture was diluted with icecold water (100 mL) and extracted with (3×100 mL) ethyl acetate.Combined organic layer was dried over sodium sulphate and concentratedunder reduced pressure to obtain crude compound. The crude compound waspurified by flash-chromatography (30% EtOAc in hexane) to afford methyl2-(4-chloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.5 g, 37%)as viscous oil. LC-MS: 308.0 (M+H).

To a solution of methyl2-(4-chloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.5 g, 8.14mmol) in anhydrous THF (50 mL) was added tert-butylsulphinamide (4.93 g,40.72 mmol) followed by titanium (IV) ethoxide (9.28 g, 40.72 mmol) andthe reaction mixture was heated to 60° C. for 2 h under argonatmosphere. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was diluted with water (50 mL),filtered through celite and washed with ethyl acetate. Organic layer wasseparated off, washed with brine, dried over anhydrous sodium sulphateand concentrated under reduced pressure to get crude compound which waspurified by flash-chromatography (30% EtOAc in hexane) to afford methyl2-[4-chloro-2-[(Z)-trifluoromethylsulfinyliminomethyl]phenyl]sulfanylpyridine-3-carboxylate(1.5 g, 45%) as an off-white solid. LC-MS: 411.1 (M+H).

To an ice-cooled suspension of LAH (0.277 g, 7.32 mmol) in THF (50 mL)was added crude methyl2-[4-chloro-2-[(Z)-trifluoromethylsulfinyliminomethyl]phenyl]sulfanylpyridine-3-carboxylate(1.5 g, 4.39 mmol) in THF (70 mL) and the reaction mixture was stirredfor 30 min at 0° C. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate solution (5 mL) and filtered through celite. The residue waswashed with ethyl acetate (3×50 mL) and the filtrate was concentrated togetN-[[5-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-1,1,1-trifluoro-methanesulfinamide(1.1 g, 65%) as an off-white solid. LC-MS: 385.0 (M+H).

To an ice-cooled solution ofN-[[5-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-1,1,1-trifluoro-methanesulfinamide(1.1 g, 2.86 mmol) in DCM (100 mL) was added Dess-Martin periodinane(1.57 g, 3.72 mmol) and the reaction mixture was stirred at roomtemperature for 1 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was poured onto saturated sodiumbicarbonate solution and extracted with DCM (3×100 mL). Combined organiclayers were washed with sodium thiosulphate, dried over sodium sulphateand concentrated under reduced pressure to get the crudeN-[[5-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-1,1,1-trifluoro-methanesulfinamide(0.750 g, 68%) as an off-white solid. LC-MS: 382.7 (M+H).

To an ice-cooled solution ofN-[[5-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-1,1,1-trifluoro-methanesulfinamide(0.750 g, 1.96 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (1.0mL) and the reaction mixture was stirred at room temperature for 1 h.Progress of the reaction was monitored by TLC. After completion,volatiles were evaporated under reduced pressure to obtain hydrochloridesalt of2-[2-(aminomethyl)-4-chloro-phenyl]sulfanylpyridine-3-carbaldehyde(0.650 g, 66%) as sticky mass. LC-MS: 279.1 (M+H).

To a suspension of2-[2-(aminomethyl)-4-chloro-phenyl]sulfanylpyridine-3-carbaldehyde(0.650 g, 2.34 mmol) in 5% aqueous NaHCO₃ solution (5 mL) was addedFmoc-OSu (0.788 g, 2.34 mmol) in CH₃CN (10 mL) and the reaction mixturewas stirred at room temperature for 4 h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith ethyl acetate (50 mL) and organic layer was separated off. Organiclayer was washed with water followed by brine and dried over anhydroussodium sulfate. Organic layer was concentrated under reduced pressure toget the crude compound. The crude compound was purified byflash-chromatography (30% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[5-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.390 g, 36%) as white solid. LC-MS: 501.0 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.24-4.18 (3H, m), 4.30 (2H, d, J=6.9 Hz),7.43-7.31 (7H, m), 7.54 (1H, d, J=7.9 Hz), 7.69 (2H, d, J=7.4 Hz),7.90-7.84 (3H, m), 8.34 (1H, dd, J=7.6, 1.7 Hz), 8.44 (1H, dd, J=4.7,1.7 Hz), 10.18 (1H, s).

Intermediate 25 9H-fluoren-9-ylmethylN-[[2-chloro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a solution 2-Chloro-6-fluoro-benzaldehyde (2.0 g, 12.89 mmol) inethanol (80 mL, argon purged) was added sodium ethoxide (2.19 g, 32.22mmol) and 2-Mercapto-nicotinic acid (2.04 g, 12.89 mmol) at roomtemperature. The reaction mixture was heated to reflux for 4 h. Progressof the reaction was monitored by TLC. After completion, volatiles wereremoved under reduced pressure to afford2-(3-chloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (6 g,crude) as brown solid which was used as such in next step withoutfurther purification. LC-MS: 294.1 (M+H).

To an ice-cooled solution of2-(3-chloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (6.0 g,crude) in DMF (25 mL) under argon atmosphere was added K₂CO₃ (2.827 g,20.46 mmol) and the reaction mixture was stirred at 0° C. for 30 min. Tothe resulting reaction mixture was added MeI (1.27 mL, 20.46 mmol) andthe reaction mixture was stirred at room temperature for 16 h. Then thereaction mixture was diluted with water (100 mL) and the aqueous phasewas extracted with ethyl acetate (50 mL×3). Combined organic layer waswashed with brine, dried over sodium sulfate and evaporated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by flash-chromatohraphy (10% ethyl acetate in hexane) toafford methyl 2-(3-chloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate(1.6 g, 40% over two steps) as yellow solid. LC-MS: 307.7 (M+H).

To a stirred solution of methyl2-(3-chloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (1.6 g, 5.20mmol) in dry THF (100 mL) under argon atmosphere was added titanium (IV)ethoxide (2.96 g, 13.00 mmol) followed by tert-butyl sulphinamide (1.57g, 13.00 mmol) and the resulting reaction mixture was heated to 60° C.for 4 h. Then the reaction mixture was cooled to room temperature,poured onto water (100 mL) and filtered through celite bed. Celite bedwas washed with ethyl acetate. Organic layer was separated off and theaqueous layer was extracted with ethyl acetate (50 mL×3). Combinedorganic layer was dried over sodium sulfate and concentrated underreduced pressure to get the crude compound. The crude compound thusobtained was purified by flash-chromatography (25% ethyl acetate inhexane) to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-chloro-phenyl]sulfanylpyridine-3-carboxylate(1.8 g, 84%) as viscous oil. LC-MS: 410.6 (M+H). As per ¹H-NMR, thiscompound is a mixture of ethyl and methyl ester. MS found: 424.9 (M+H).

To an ice-cooled solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-chloro-phenyl]sulfanylpyridine-3-carboxylate(1.8 g, 4.38 mmol) in THF (50 mL) under argon atmosphere was added LAH(0.416 g, 10.95 mmol) portion-wise and the reaction mixture was stirredat 0° C. for 1 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with ethyl acetate andsaturated sodium sulfate solution. Then the reaction mixture wasfiltered through celite and washed with EtOAc. Filtrate was concentratedto getN-[[2-chloro-6-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 95%) as an off-white solid. LC-MS: 384.9 (M+H).

To an ice-cooled solution ofN-[[2-chloro-6-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 4.15 mmol) in DCM (50 mL) was added Dess Martin periodinane(2.227 g, 5.40 mmol) portion-wise and the reaction mixture was stirredat room temperature for 2 h under argon atmosphere. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with DCM (50 mL) and saturated solution of sodiumbicarbonate (50 mL). Organic layer was separated off and the aqueouslayer was extracted with DCM (50 mL×2). Combined organic layer waswashed with sodium thiosulphate solution followed by brine. Volatileswere removed under reduced pressure to getN-[[2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g) as viscous oil. LC-MS: 382.9 (M+H).

To an ice-cooled solution ofN-[[2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, crude) in dioxane (20 mL) was added 4M HCl in dioxane (30 mL)and the reaction mixture was stirred at room temperature for a period of2 h. Progress of the reaction was monitored by LCMS. Volatiles wereremoved under reduced pressure to get the crude compound which waswashed with diethyl ether (30 mL×2) and dried well to get2-[2-(aminomethyl)-3-chloro-phenyl]sulfanylpyridine-3-carbaldehyde (2.0g, crude) as yellow solid. LC-MS: 279.1 (M+H).

To a stirred suspension of crude2-[2-(aminomethyl)-3-chloro-phenyl]sulfanylpyridine-3-carbaldehyde (2.0g, crude) in 5% sodium bicarbonate solution and acetonitrile (30 mL,1:1) was added Fmoc-OSu (1.08 g, 3.21 mmol) in acetonitrile (15 mL) andthe reaction mixture was stirred at room temperature for 3 h. Progressof the reaction was monitored by TLC. After completion, volatiles wereremoved under reduced pressure and the crude reaction mixture wasdiluted with water (50 mL). The aqueous phase was extracted with ethylacetate (50 mL×3). Combined organic layer was washed with brine (50mL×1), dried over anhydrous sodium sulfate and evaporated under reducedpressure to get crude compound. The crude compound thus obtained waspurified by flash-chromatography (30% ethyl acetate in hexane) to afforddesired compound which was further washed with ethyl acetate (5 mL) anddried to get 9H-fluoren-9-ylmethylN-[[2-chloro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.515 g, 20% over two steps) as white solid. LC-MS: 500.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.19-4.15 (3H, m), 4.36 (2H, d, J=4.6 Hz),7.30 (2H, t, J=7.4 Hz), 7.42-7.34 (4H, m), 7.47 (1H, t, J=4.5 Hz), 7.53(1H, d, J=7.0 Hz), 7.61 (1H, d, J=7.9 Hz), 7.67 (2H, s, J=7.4 Hz), 7.88(2H, d, J=7.5 Hz), 8.33 (1H, dd, J=7.6, 1.7 Hz), 8.44 (1H, dd, J=4.7,1.7 Hz), 10.18 (1H, s).

Intermediate 26 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-(4-fluoro-2-formyl-phenyl)sulfanyl-phenyl]methyl]carbamate

To a stirred solution of 5-Fluoro-2-mercapto-benzoic acid (1 g, 5.808mmol) in THF (20 mL), was added 2,2,2-Trichloro-acetimidic acidtert-butyl ester (3.6 mL, 20.328 mmol) followed by slow addition ofBF₃.OEt₂ (0.615 mL, 5.808 mmol) at 0° C. and stirred at 25° C. for 2 h.

After completion of reaction, reaction mixture was quenched with waterand extracted with ethyl acetate. The combined organic layer was washedwith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to get crude which was purified by normal silica columnusing 2% ethyl acetate in hexane to afford tert-butyl5-fluoro-2-sulfanyl-benzoate (620 mg, 47%) as a colourless liquid.

To a stirred solution tert-butyl 5-fluoro-2-sulfanyl-benzoate (600 mg,2.628 mmol) in DMF (10 mL) were added 2,3,5-Trichloro-benzaldehyde (660mg, 3.154 mmol), Cs₂CO₃ (2.13 g, 6.571 mmol) and reaction mixture washeated 60° C. for 3 h. After completion of reaction, reaction mixturewas quenched with water and extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure to get crude which was purifiedby normal silica column using 2% ethyl acetate in hexane to affordtert-butyl 2-(2,4-dichloro-6-formyl-phenyl)sulfanyl-5-fluoro-benzoate(660 mg, 62%) as a colorless liquid.

To a stirred solution of2-(2,4-dichloro-6-formyl-phenyl)sulfanyl-5-fluoro-benzoate (900 mg,2.243 mmol) in THF (20 mL) were added 2-methyl 2-propane sulfonamide(271 mg, 2.243 mmol) and Ti(OEt)₄ (2.3 mL, 11.214 mmol) and heated to70° C. for 16 h. Reaction mixture was quenched with brine solution andextracted with ethyl acetate. The separated organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum to affordtert-butyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4,6-dichloro-phenyl]sulfanyl-5-fluoro-benzoate(1 g, crude) as a yellow liquid. MS found: 504.1 (M+H).

To a stirred solution of tert-butyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4,6-dichloro-phenyl]sulfanyl-5-fluoro-benzoate(1 g, 1.982 mmol) in THF (20 mL) was added LiBH₄(215 mg, 9.911 mmol) andreaction mass was heated to 50° C. for 4 h. Reaction mass was quenchedwith saturated ammonium chloride and extracted with ethyl acetate. Theseparated organic layer washed with brine solution, dried over anhydroussodium sulfate and evaporated under reduced pressure to getN-[[3,5-dichloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.2 g, crude) as a off white solid. MS found: 435.7 (M+H).

To a stirred solution ofN-[[3,5-dichloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.2 g, 2.75 mmol) in MeOH (20 mL), was added 4M HCl/dioxane (10 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-4,6-dichloro-phenyl]sulfanyl-5-fluoro-phenyl]methanol(1 g, crude) as a off white solid. MS found: 332 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-4,6-dichloro-phenyl]sulfanyl-5-fluoro-phenyl]methanol(1 g, 2.712 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc OSU (914 mg, 2.712mmol) in CH₃CN (20 mL) at 25° C. and reaction was stirred at 25° C. for2 h. Then reaction mass was diluted with water and extracted with ethylacetate. The separated organic layer was washed with brine solution,dried over sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by normal silica column using 5-30%ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(800 mg, 64%, 4 steps) as a off white solid. MS found: 554 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(800 mg, 1.661 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂ (2.88 g,33.221 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mixture was filtered through celite pad; filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-(4-fluoro-2-formyl-phenyl)sulfanyl-phenyl]methyl]carbamate(700 mg, 76%) as an off white solid. MS found: 552.3 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.17-4.12 (3H, m), 4.35 (2H, d, J=5.1 Hz),7.45-7.28 (6H, m), 7.67-7.60 (4H, m), 7.88 (2H, d, J=7.5 Hz), 8.35 (1H,dd, J=7.6, 1.8 Hz), 8.41 (1H, dd, J=4.8, 1.8 Hz), 10.19 (1H, s).

Intermediate 27 and Intermediate 28 9H-fluoren-9-ylmethylN-[[3-chloro-6-fluoro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

and 9H-fluoren-9-ylmethylN-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a solution 3-chloro-2,6-difluoro-benzaldehyde (2.0 g, 12.88 mmol) inethanol (80 mL, argon purged) was added sodium ethoxide (2.192 g, 32.21mmol) and 2-Mercapto-nicotinic acid (2.26 g, 12.88 mmol) at roomtemperature and the reaction mixture was heated to reflux for 4 h.Progress of the reaction was monitored by TLC. After completion,volatiles were removed under reduced pressure to afford a mixture of2-(6-chloro-3-fluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acidand 2-(4-chloro-3-fluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylicacid (6 g, crude) as brown solid which was used as such in next stepwithout further purification. LC-MS: 312.1 (M+H).

To an ice-cooled solution of above mentioned mixture (6.0 g, crude) inDMF (25 mL) under argon atmosphere was added K₂CO₃ (2.66 g, 19.24 mmol)and the reaction mixture was stirred at 0° C. for 30 min. To theresulting reaction mixture was added MeI (1.198 mL, 19.248 mmol) and thereaction mixture was stirred at room temperature for 16 h. Then thereaction mixture was diluted with water (100 mL) and the aqueous phasewas extracted with ethyl acetate (50 mL×3). Combined organic layer waswashed with brine, dried over sodium sulfate and evaporated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by flash-chromatography (10% ethyl acetate in hexane) toafford a mixture of methyl2-(4-chloro-3-fluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate andmethyl2-(4-chloro-3-fluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.3g, 57% over two steps) as yellow solid. LC-MS: 325.7 (M+H).

To a stirred solution of of above mentioned mixture (2.3 g, 7.06 mmol)in dry THF (100 mL) under argon atmosphere was added titanium(IV)ethoxide (4.027 g, 17.65 mmol) followed by tert-butyl sulphinamide(2.139 g, 17.65 mmol) and the resulting reaction mixture was stirred atroom temperature for 1 h and heated to 60° C. for 4 h. Then the reactionmixture was cooled to room temperature, poured onto water (100 mL) andfiltered through celite bed. Celite bed was washed with ethyl acetate.Organic layer was separated off and the aqueous layer was extracted withethyl acetate (50 mL×3). Combined organic layer was dried over sodiumsulfate and concentrated under reduced pressure to get the crudecompound. The crude compound thus obtained was purified byflash-chromatography (25% ethyl acetate in hexane) to afford a mixtureof methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-chloro-3-fluoro-phenyl]sulfanylpyridine-3-carboxylateand methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-chloro-3-fluoro-phenyl]sulfanylpyridine-3-carboxylate(1.9 g, 63%) as viscous oil. LC-MS: 428.6 (M+H).

To an ice-cooled solution of above mentioned mixture (1.9 g, 4.43 mmol)in THF (50 mL) under argon atmosphere was added LAH (0.42 g, 11.07 mmol)portion wise and the reaction mixture was stirred at 0° C. for 1 h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was quenched with ethyl acetate and saturated sodiumsulfate solution. Then the reaction mixture was filtered through celiteand washed with EtOAc. Filtrate was concentrated to get a mixture ofN-[[3-chloro-2-fluoro-6-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamideandN-[[3-chloro-2-fluoro-6-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, 90%) as an off-white solid. LC-MS: 402.9 (M+H).

To an ice-cooled solution of above mentioned mixture (1.6 g, 3.97 mmol)in DCM (50 mL) was added Dess Martin periodinane (2.128 g, 5.162 mmol)portion-wise and the reaction mixture was stirred at room temperaturefor 2 h under argon atmosphere. Progress of the reaction was monitoredby TLC. After completion, the reaction mixture was diluted with DCM (50mL) and saturated solution of sodium bicarbonate (50 mL). Organic layerwas separated off and the aqueous layer was extracted with DCM (50mL×2). Combined organic layer was washed with sodium thiosulphatesolution followed by brine. Volatiles were removed under reducedpressure to get a mixture ofN-[[2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamideandN-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.6 g, quan) as viscous oil. LC-MS: 400.8 (M+H).

To an ice-cooled solution of above mentioned mixture (2.0 g, crude) indioxane (20 mL) was added 4M HCl in dioxane (30 mL) and the reactionmixture was stirred at room temperature for a period of 2 h. Progress ofthe reaction was monitored by LCMS. Volatiles were removed under reducedpressure to get the crude compound which was washed with diethyl ether(30 mL×2) and dried to get a mixture of2-[2-(aminomethyl)-4-chloro-3-fluoro-phenyl]sulfanylpyridine-3-carbaldehydeand2-[2-(aminomethyl)-4-chloro-3-fluoro-phenyl]sulfanylpyridine-3-carbaldehyde(2.0 g, crude) as yellow solid. LC-MS: 297.1 (M+H).

To a stirred suspension of above mentioned mixture (2.0 g, crude) in 5%sodium bicarbonate solution and acetonitrile (30 mL, 1:1) was addedFmoc-OSu (1.422 g, 4.21 mmol) in acetonitrile (15 mL) and the reactionmixture was stirred at room temperature for 3 h. Progress of thereaction was monitored by TLC. After completion, volatiles were removedunder reduced pressure and the crude reaction mixture was diluted withwater (50 mL). The aqueous phase was extracted with ethyl acetate (50mL×3). Combined organic layer was washed with brine (50 mL×1), driedover anhydrous sodium sulfate and evaporated under reduced pressure toget crude compound. The crude compound thus obtained was purified byflash-chromatography (20% ethyl acetate in hexane) to afford a mixtureof two isomers 1.6 g. The mixture of isomers was purified by prep HPLCto get 9H-fluoren-9-ylmethylN-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.910 g, 35% over two steps) as white solid and 9H-fluoren-9-ylmethylN-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.210 g, 8% over two steps) as white solid. LC-MS: 518.9 (M+H). andLC-MS: 519.0 (M+H).

¹H-NMR 9H-fluoren-9-ylmethylN-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate:(400 MHz, DMSO-d6): δ 4.17-4.12 (3H, m), 4.35 (2H, d, J=5.1 Hz),7.45-7.28 (6H, m), 7.67-7.60 (4H, m), 7.88 (2H, d, J=7.5 Hz), 8.35 (1H,dd, J=7.6, 1.8 Hz), 8.41 (1H, dd, J=4.8, 1.8 Hz), 10.19 (1H, s).

¹H-NMR 9H-fluoren-9-ylmethylN-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate:(400 MHz, DMSO-d6): δ 4.18-4.13 (3H, m), 4.27 (2H, d, J=4.2 Hz), 7.30(2H, t, J=7.4 Hz), 7.42-7.34 (4H, m), 7.66-7.60 (4H, m), 7.9 (2H, d,J=7.5 Hz), 8.34 (1H, dd, J=7.6, 1.8 Hz), 8.44 (1H, dd, J=4.8, 1.8 Hz),10.18 (1H, s).

Intermediate 29 9H-fluoren-9-ylmethylN-[[2,3-dichloro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To an ice-cooled solution of 2,3-Dichloro-6-fluoro-benzaldehyde (2 g,12.88 mmol) in ethanol (20 mL) were added sodium ethoxide (2.1 g, 32.22mmol) and 2-Mercapto-nicotinic acid (2.7 g, 14.17 mmol) sequentially andthe reaction mixture was heated to 90° C. for 5 h. Progress of thereaction was monitored by TLC. Volatiles were removed under reducedpressure to get2-(3,4-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (6.8g, crude) as pale yellow solid which was used as such in next stepwithout further purification.

To an ice-cooled solution of2-(3,4-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (4.2g, crude) in DMF (30 mL) were added potassium carbonate (4.4 g, 32.10mmol) and methyl iodide (2.3 mL, 38.52 mmol) sequentially and thereaction mixture was stirred at room temperature for 15 h. Progress ofthe reaction was monitored by TLC. Then the reaction mixture was dilutedwith water (50 mL) and the aqueous phase was extracted with ethylacetate (50 mL×2). Combined organic layer was washed with brine solution(50 mL×2), dried over anhydrous sodium sulfate and solvent distilled-offunder reduced pressure to get crude compound which was purified byflash-chromatography to get methyl2-(3,4-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.5 g,56% over two steps) as pale yellow solid.

To a stirred solution of methyl2-(3,4-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.5 g,7.30 mmol) in anhydrous THF (40 mL) were added2-methylpropane-2-sulfinamide (1.7 g, 14.61 mmol) and titaniumtetraethoxide (3.33 g, 14.61 mmol). The resultant reaction mixture washeated to 60° C. for a period of 1 h under argon atmosphere. Then thereaction mixture was cooled to ambient temperature, poured ontoice-water and filtered through a short pad of celite. Filtrate wasextracted with ethyl acetate (100 mL×2), washed with brine (100 mL×2),dried over sodium sulfate and concentrated under reduced pressure to getthe crude compound which was purified by flash-chromatography (gradient10-20% ethyl acetate in hexane) to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,4-dichloro-phenyl]sulfanylpyridine-3-carboxylate(1.9 g, 58%) as pale orange solid. LC-MS: 444.6 (M+H).

To an ice-cooled solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,4-dichloro-phenyl]sulfanylpyridine-3-carboxylate(2.2 g, 4.93 mmol) in THF (30 mL) under argon atmosphere was added LAH(0.375 g, 9.879 mmol) portion-wise and the reaction mixture was stirredat room temperature for 45 min. Progress of the reaction was monitoredby TLC. After completion, the reaction mixture was quenched withsaturated ammonium chloride solution (˜5 mL), filtered through celitebed and bed was washed with ethyl acetate. Filtrate was concentrated togetN-[[2,3-dichloro-6-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 96%) as off-white solid. LC-MS: 418.6 (M+H).

To an ice-cooled solution ofN-[[2,3-dichloro-6-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.1 g, 5.01 mmol) in DCM (20 mL) was added Dess-Martin periodinane (2.7g, 6.51 mmol) portion-wise and the reaction mixture was stirred at roomtemperature for a period of 2 h under argon atmosphere. Progress of thereaction was monitored by TLC. The resulting reaction mixture wasdiluted with diethyl ether (25 mL) and poured into a saturated solutionof sodium bicarbonate (30 mL) containing sodium thiosulphate (4 g) andstirred until two distinct layers were observed. Organic layer wasseparated off and the aqueous phase was extracted with ethyl acetate (50mL×2). Combined organic layer was washed with saturated aqueous sodiumbicarbonate solution (50 mL×2) followed by brine (25 mL×2). Organiclayer dried over anhydrous sodium sulfate and concentrated under reducedpressure to getN-[[2,3-dichloro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 95%) as pale yellow solid which was used as such in next stepwithout further purification. LC-MS: 416.7 (M+H).

To a solution ofN-[[2,3-dichloro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 4.79 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (2.0mL) slowly and the resultant reaction mixture was stirred at ambienttemperature for 2 h. Progress of the reaction was monitored by TLC.Volatiles were removed under reduced pressure to get crude compoundwhich was washed with diethyl ether and dried to get2-[2-(aminomethyl)-3,4-dichloro-phenyl]sulfanylpyridine-3-carbaldehyde(1.6 g, crude) as pale yellow solid. This compound was used as such inthe next step without further purification. LC-MS: 313.1 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-3,4-dichloro-phenyl]sulfanylpyridine-3-carbaldehyde(1.6 g, crude) in 5% sodium bicarbonate (15 mL) was added Fmoc-OSU (1.8g, 5.62 mmol) in acetonitrile (2 mL) and the reaction mixture wasstirred at room temperature for 3 h. Then the reaction mixture wasdiluted with ethyl acetate (50 mL) and washed with brine (50 mL×1),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude compound thus obtained was purified by combiflash(30% ethyl acetate in hexane) to afford 9H-fluoren-9-ylmethylN-[[2,3-dichloro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(1.0 g, 40% over two steps) as an off-white solid. LC-MS: 534.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.33-4.13 (3H, m), 4.39 (2H, d, J=4.5 Hz),7.30 (2H, t, J=7.4 Hz), 7.42-7.35 (3H, m), 7.55-7.53 (2H, m), 7.69-7.66(3H, m), 7.88 (2H, d, J=7.5 Hz), 8.34 (1H, dd, J=7.6, 1.4 Hz), 8.45 (1H,dd, J=4.8, 1.7 Hz), 10.17 (1H, s).

Intermediate 30 9H-fluoren-9-ylmethylN-[[3,6-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To an ice-cooled solution of 3,6-Dichloro-2-fluoro-benzaldehyde (2 g,12.88 mmol) in ethanol (30 mL) was added sodium ethoxide (2.1 g, 32.22mmol) and 2-Mercapto-nicotinic acid (2.7 g, 14.17 mmol) sequentially andthe reaction mixture was heated to 90° C. for 5 h. Progress of thereaction was monitored by TLC. Volatiles were removed under reducedpressure to get2-(3,6-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (6.8g, crude) as pale yellow solid which was used as such in next stepwithout further purification.

To a solution of2-(3,6-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (4.2g, crude) in DMF (30 mL) was added potassium carbonate (4.42 g, 31.99mmol) and methyl iodide (2.3 mL, 38.39 mmol) sequentially and thereaction mixture was stirred at room temperature for 15 h. Progress ofthe reaction was monitored by TLC. Then the reaction mixture was dilutedwith water (50 mL) and extracted with ethyl acetate (50 mL×2). Combinedorganic layers were washed with brine solution (50 mL×2), dried overanhydrous sodium sulfate and solvent distilled-off under reducedpressure to get crude compound which was purified byflash-chromatography to get methyl2-(3,6-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.6 g,60% over two steps) as pale yellow oil.

To a stirred solution of methyl2-(3,6-dichloro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.6 g,7.598 mmol) in anhydrous THF (40 mL) were added2-methylpropane-2-sulfinamide (1.8 g, 15.19 mmol) and titaniumtetraethoxide (3.4 g, 15.19 mmol). The resultant reaction mixture washeated to 60° C. for 1 h under argon atmosphere. Then the reactionmixture was then cooled to ambient temperature, poured onto ice-waterand filtered through a short pad of celite. Filtrate was extracted withethyl acetate (100 mL×2), washed with brine (100 mL×2), dried oversodium sulfate and concentrated under reduced pressure to get the crudecompound which was purified by flash-chromatography (gradient 10-20%ethyl acetate in hexane) to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-dichloro-phenyl]sulfanylpyridine-3-carboxylate(2 g, 59%) as pale orange solid. LC-MS: 444.9 (M+H).

To an ice-cooled solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-dichloro-phenyl]sulfanylpyridine-3-carboxylate(2.2 g, 4.93 mmol) in THF (40 mL) under argon atmosphere was added LAH(0.37 g, 9.87 mmol) portion-wise and the reaction mixture was stirred atroom temperature for 1 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was quenched with saturatedAmmonium chloride solution (˜5 mL), filtered through celite bed and bedwas washed with EtOAc. Filtrate was concentrated to getN-[[3,6-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 96%) as off-white solid. LC-MS: 418.9 (M+H).

To an ice-cooled solution ofN-[[3,6-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.1 g, 5.01 mmol) in DCM (20 mL) was added Dess-Martin periodinane (2.7g, 6.50 mmol) portion-wise and the reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. The resulting reaction mixture was diluted withdiethyl ether (25 mL) and poured onto a solution of saturated solutionof sodium bicarbonate (30 mL) containing sodium thiosulphate (4 g) andstirred until two distinct layers were observed. Organic layer wasseparated off and the aqueous phase was extracted with ethyl acetate (50mL×2). Combined organic layer was washed with saturated aqueous sodiumbicarbonate solution (50 mL×2) followed by brine (25 mL×2). Organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to getN-[[3,6-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 95%) as pale brown oil which was used as such in next stepwithout further purification. LC-MS: 416.7 (M+H).

To a solution ofN-[[3,6-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, crude) in dioxane (20 mL) was added 4 M HCl in dioxane (2.0 mL)dropwise and the reaction mixture was stirred at room temperature for 2h. Progress of the reaction was monitored by TLC. Volatiles were removedunder reduced pressure to get crude compound which was washed withdiethyl ether and dried to get2-[2-(aminomethyl)-3,6-dichloro-phenyl]sulfanylpyridine-3-carbaldehyde(1.8 g, crude) as pale yellow solid. This compound was used as such innext step without further purification. LC-MS: 313.0 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-3,6-dichloro-phenyl]sulfanylpyridine-3-carbaldehyde(1.8 g, crude) in 5% sodium bicarbonate (15 mL) was added Fmoc-OSU (2.1g, 6.322 mmol) in acetonitrile (25 mL) and the reaction mixture wasstirred at room temperature for 3 h. Then the reaction mixture wasdiluted with ethyl acetate (50 mL) and washed with brine (50 mL×1),dried over anhydrous sodium sulfate and evaporated under reducedpressure to get the crude compound. The crude compound thus obtained waspurified by flash-chromatography (30% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[3,6-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.98 g, 38% over two steps) as an off-white solid. LC-MS: 534.8 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.21-4.14 (3H, m), 4.45 (2H, d, J=4.4 Hz),7.31 (2H, t, J=7.32 Hz), 7.42-7.35 (3H, m), 7.55 (1H, t, J=4.4 Hz),7.68-7.62 (4H, m), 7.88 (2H, d, J=7.52 Hz), 8.36 (1H, dd, J=7.52, 1.48Hz), 8.43 (1H, dd, J=4.8, 1.76 Hz), 10.19 (1H, s).

Intermediate 31 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(trifluoromethyl)phenyl]methyl]carbamate

To an ice-cooled solution of NaH (1.13 g, 27.80 mmol) in DMF (10 mL) wasadded 2-thionicotinic acid (2.15 g, 13.90 mmol) in DMF (10 mL) and thereaction mixture was stirred for 15 min. To the resulting reactionmixture was added a solution of 3-Chloro-2-fluoro-6-methyl-benzaldehyde(2.1 g, 9.26 mmol) in DMF (10 mL) and the reaction mixture was stirredat room temperature for 9 h. Then the reaction mixture was cooled to 0°C. and K₂CO₃ (3.84 g, 27.80 mmol) followed by methyl iodide (3.10 mL,27.80 mmol) were added. The resulting reaction mixture was stirred atroom temperature for 16 h. Then the reaction mixture was quenched bysaturated NH₄Cl solution (20 mL) and extracted with ethyl acetate (60mL). Organic layer was separated off, washed with water (2×30 mL)followed by brine (2×30 mL) and dried over anhydrous sodium sulfate.Organic layer was concentrated under reduced pressure and the crudecompound was purified by flash-chromatography to afford methyl2-[6-chloro-2-formyl-3-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.3 g, 37%) as an off-white solid. LC-MS: 375.7 (M+H).

To a degassed solution of methyl2-[6-chloro-2-formyl-3-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.4 g, 3.72 mmol) in THF (30 mL) was added titanium (IV) ethoxide (8.49g, 37.25 mmol) followed by tert-butyl sulphinamide (4.50 g, 37.25 mmol)and the resulting reaction mixture was heated to 60° C. for 2 h. Thenthe reaction mixture was diluted with water (30 mL) and extracted withEtOAc (70 mL). Organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-3-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.25 g, 70%) as an off-white solid. It's a mixture of ethyl and methylester. MS found: 478.7 (M+H).

To an ice-cooled solution of LAH (0.297 g, 7.83 mmol) in THF (10 mL) wasadded methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-3-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(1.25 g, 2.61 mmol) in THF (15 mL) and the reaction mixture was stirredfor 0.5 h at same temperature. Then the reaction mixture was quenched bysaturated sodium sulfate solution (2 mL) and EtOAc (80 mL). The reactionmixture was filtered through celite and filtrate was concentrated underreduced pressure to affordN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.1 g, 93%) as an off-white solid. MS found: 452.8 (M+H).

To an ice-cooled solution ofN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.1 g, 2.42 mmol) in DCM (30 mL) was added Dess-Martin periodinane(2.06 g, 4.85 mmol) and the reaction mixture was allowed to stir atambient temperature for 1 h. Progress of the reaction was monitored byTLC. After completion, the reaction mixture was poured onto saturatedsodium bicarbonate solution and extracted with DCM (3×50 mL). Combinedorganic layer was washed with sodium thiosulphate, dried over sodiumsulfate and concentrated under reduced pressure to affordN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.0 g, 91%) as an off-white solid. MS found: 450.8 (M+H).

To an ice-cooled solution ofN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.2 g, 2.66 mmol) in dioxane (20 mL) was added 4 M HCl in dioxane (15mL) and the reaction mixture was allowed to stir at ambient temperaturefor 1 h. TLC showed consumption of starting material. Volatiles wereevaporated under reduced pressure to obtain2-[2-(aminomethyl)-6-chloro-3-(trifluoromethyl)phenyl]sulfanylpyridine-3-carbaldehyde(0.91 g, 99%) as an off-white solid.

To an ice-cooled suspension of2-[2-(aminomethyl)-6-chloro-3-(trifluoromethyl)phenyl]sulfanylpyridine-3-carbaldehyde(0.91 g, 2.62 mmol) in acetonitrile (15 mL) were added 5% aqueous NaHCO₃solution (12 mL) and Fmoc-OSu (0.708 g, 2.09 mmol) in CH₃CN (15 mL) andthe reaction mixture was stirred at ambient temperature for 4 h. It wasthen diluted with ethyl acetate (80 mL) and water (30 mL). Organic layerwas separated off, washed with water, brine and dried over anhydroussodium sulfate. Organic layer was concentrated under reduced pressure toget the crude compound which was purified by flash-chromatography toafford 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(trifluoromethyl)phenyl]methyl]carbamate(0.590 g, 40%) as an off-white solid. LC-MS: 569.0 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 4.21-4.16 (3H, m), 4.43 (2H, br s),7.33-7.29 (2H, m), 7.43-7.36 (3H, m), 7.56 (1H, br s), 7.66 (2H, m),7.94-7.84 (4H, m), 8.38 (1H, d, J=7.4 Hz), 8.43 (1H, d, J=3.8 Hz), 10.19(1H, s).

Intermediate 32 9H-fluoren-9-ylmethylN-[[3,6-difluoro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a solution 2-thionicotinic acid (4.0 g, 25.77 mmol) in ethanol (80mL, argon purged) were added sodium ethoxide (4.385 g, 64.437 mmol) and2,3,6-Trifluoro-benzaldehyde (4.95 g, 30.93 mmol) sequentially and thereaction mixture was heated to reflux for 4 h. Progress of the reactionwas monitored by TLC. After completion, volatiles were removed underreduced pressure to afford2-(3,6-difluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (12g, crude) as brown solid which was used as such in next step withoutfurther purification. LC-MS: 296.1 (M+H).

To an ice-cooled solution of2-(3,6-difluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid (12.0g, crude) in DMF (25 mL) under argon atmosphere was added K₂CO₃ (5.617g, 40.64 mmol) and the reaction mixture was stirred at 0° C. for 30 min.To the resulting reaction mixture was added MeI (2.53 mL, 40.64 mmol)and the reaction mixture was stirred at room temperature for 16 h. Thenthe reaction mixture was diluted with water (100 mL) and the aqueousphase was extracted with ethyl acetate (50 mL×3). Combined organic layerwas washed with brine, dried over sodium sulfate and evaporated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by combiflash (10% ethyl acetate in hexane) to affordmethyl 2-(3,6-difluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate(2.3 g, 29% over two steps) as yellow solid. LC-MS: 311.1 (M+2H), MSfound: 310.1 (M+H).

To a stirred solution of methyl2-(3,6-difluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.3 g,7.43 mmol) in dry THF (100 mL) under argon atmosphere was addedtitanium(IV) ethoxide (4.24 g, 18.59 mmol) followed by tert-butylsulphinamide (2.25 g, 18.59 mmol). The resulting reaction mixture wasstirred at room temperature for 1 h and heated to 60° C. for 4 h. Thenthe reaction mixture was cooled to room temperature, poured onto water(100 mL) and filtered through celite bed. Celite bed was washed withethyl acetate. Organic layer was separated off and the aqueous layer wasextracted with ethyl acetate (50 mL×3). Combined organic layer was driedover sodium sulfate and concentrated under reduced pressure to get thecrude compound. The crude compound thus obtained was purified bycombiflash (25% ethyl acetate in hexane) to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-difluoro-phenyl]sulfanylpyridine-3-carboxylate(1.6 g, 52%) as viscous oil. LC-MS: 412.6 (M+H).

To an ice-cooled solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3,6-difluoro-phenyl]sulfanylpyridine-3-carboxylate(1.6 g, 3.88 mmol) in THF (30 mL) under argon atmosphere was added LAH(0.368 g, 9.70 mmol) portion wise and the reaction mixture was stirredat 0° C. for 1 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with ethyl acetate andsaturated sodium sulfate solution. Then the reaction mixture wasfiltered through celite and washed with EtOAc. Filtrate was concentratedto getN-[[3,6-difluoro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 94%) as an off-white solid. LC-MS: 387.0 (M+H).

To an ice-cooled solution ofN-[[3,6-difluoro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 3.62 mmol) in DCM (50 mL) was added Dess-Martin periodinane(2.239 g, 5.43 mmol) portion-wise and the reaction mixture was stirredat room temperature for 2 h under argon atmosphere. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with DCM (50 mL) and saturated solution of sodiumbicarbonate (50 mL). Organic layer was separated off and the aqueouslayer was extracted with DCM (50 mL×2). Combined organic layers werewashed with sodium thiosulfate solution followed by brine. Volatileswere removed under reduced pressure to getN-[[3,6-difluoro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, quant) as viscous oil. LC-MS: 384.9 (M+H).

To an ice-cooled solution ofN-[[3,6-difluoro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 4.14 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (30mL) and the reaction mixture was stirred at room temperature for aperiod of 2 h. Progress of the reaction was monitored by LC-MS.Volatiles were removed under reduced pressure to get the crude compoundwhich was washed with diethyl ether (30 mL×2) and dried well to get2-[2-(aminomethyl)-3,6-difluoro-phenyl]sulfanylpyridine-3-carbaldehyde(1.6 g, crude) as yellow solid. LC-MS: 281.0 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-3,6-difluoro-phenyl]sulfanylpyridine-3-carbaldehyde(1.6 g, crude) in 5% sodium bicarbonate solution and acetonitrile (30mL, 1:1) was added Fmoc-OSu (1.08 g, 3.21 mmol) in acetonitrile (15 mL)and the reaction mixture was stirred at room temperature for 3 h.Progress of the reaction was monitored by TLC. After completion,volatiles were removed under reduced pressure and the crude reactionmixture was diluted with water (50 mL). The aqueous phase was extractedwith ethyl acetate (50 mL×3). Combined organic layer was washed withbrine (50 mL×1), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to get crude compound. The crude compound thusobtained was purified by flash-chromatography (20% ethyl acetate inhexane) to afford desired compound which was further washed withn-pentane (5 mL) and dried to get 9H-fluoren-9-ylmethylN-[[3,6-difluoro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.85 g, 47% over two steps) as white solid. LC-MS: 502.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.20-4.11 (3H, m), 4.32 (2H, d, J=4.2 Hz),7.30 (2H, m), 7.47-7.35 (5H, m), 7.66-7.64 (3H, m), 7.87 (2H, d, J=7.5Hz), 8.35 (1H, dd, J=7.6, 1.8 Hz), 8.42 (1H, dd, J=4.8, 1.8 Hz), 10.18(1H, s).

Intermediate 33 9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-methoxy-phenyl]methyl]carbamate

To a stirred solution of 3-Chloro-2-hydroxy-5-methoxy-benzaldehyde (2.4g, 12.903 mmol) in DCM (25 mL) was added Et₃N (2.72 ml, 19.355 mmol),triflic anhydride (3.27 ml, 19.355 mmol) at −5° C. and reaction mass wasstirred at −5° C. for 30 min. Reaction mass was diluted with DCM andwashed with saturated sodium bicarbonate solution. The separated organiclayer was washed with brine solution, dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The crude thus obtainedwas purified by normal silica column using 0-8% ethyl acetate in hexaneto get (2-chloro-6-formyl-4-methoxy-phenyl) trifluoromethanesulfonate(2.4 g, 58%) as a colorless liquid.

To a stirred and degassed solution of(2-chloro-6-formyl-4-methoxy-phenyl) trifluoromethanesulfonate (2.915 g,9.167 mmol) in dioxan (25 mL) were added DIPEA (3.159 ml, 18.333 mmol),Xanthphos (165.205 mg, 0.458 mmol), Pd₂(dba)₃ (209.848 mg, 0.229 mmol),methyl 2-sulfanylbenzoate (770 mg, 4.583 mmol) and reaction mass washeated to 110° C. for 2.5 h. Reaction mixture was filtered throughcelite pad, washed with ethyl acetate and filtrate evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 0-3% ethyl acetate and hexane to get methyl2-(2-chloro-6-formyl-4-methoxy-phenyl)sulfanylbenzoate (1.2 g, 78%) as alight yellow solid.

To a stirred solution of methyl2-(2-chloro-6-formyl-4-methoxy-phenyl)sulfanylbenzoate (1.2 g, 3.571mmol) in THF (25 mL) was added 2-methylpropane-2-sulfinamide (433 mg,3.571 mmol), Ti(OEt)₄(3.74 mL, 17.857 mmol) and reaction mass was heatedto 70° C. for 4 h. The reaction mass was quenched with saturated sodiumchloride solution, solid obtained was filtered through celite pad,washed with ethyl acetate. The separated organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure to getethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-4-methoxy-phenyl]sulfanylbenzoate(1.8 g crude) which was directly used for next step without furtherpurification. MS found: 453.8 (M+H).

To a stirred solution of ethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-4-methoxy-phenyl]sulfanylbenzoate(1.8 g, 3.974 mmol) in THF (25 mL) was added LiBH₄ (0.865 g, 39.735mmol) at 0° C. and reaction mass was heated to 50° C. for 4 h. Thesolvent was evaporated and the reaction mass was quenched with NH₄Cl andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over sodium sulfate and evaporated underreduced pressure to getN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g crude) which was directly used for next step without furtherpurification. MS found: 413.9 (M+H).

To a stirred solution ofN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 3.39 mmol) in MeOH (25 mL), was added 4M HCl in dioxane (12 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to[2-[2-(aminomethyl)-6-chloro-4-methoxy-phenyl]sulfanylphenyl]methanol(1.4 g, crude) which was directly used for next step without furtherpurification. MS found: 310.0 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-4-methoxy-phenyl]sulfanylphenyl]methanol(1.4 g, 4.531 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (1.528 g,4.531 mmol) in CH₃CN (20 mL) at 25° C. and reaction mixture was stirredat 25° C. for 2 h. Then reaction mass was diluted with water andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to 9H-fluoren-9-ylmethylN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-phenyl]methyl]carbamate(1.4 g, crude) as a off white solid. MS found: 531.8 (M+H).

To a stirred solution ofN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-phenyl]methyl]carbamate(1.4 g, 2.637 mmol) in DCM/THF (1:1, 50 mL) was added MnO₂(4.584 g,52.731 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 0-13% ethyl acetate in hexane to9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-methoxy-phenyl]methyl]carbamate(600 mg, 32%, 5 steps) as a off white solid.

¹H-NMR: (400 MHz, DMSO-d6) δ 3.84 (3H; s); 4.20-4.29 (5H; m); 6.51 (1H;d; J=8.0 Hz); 6.97 (1H; br s); 7.26 (1H; br s); 7.33-7.36 (3H; m);7.399-7.44 (2H; m); 7.69 (2H; d; J=7.40 Hz); 7.80 (1H; m); 7.89 (2H; d;J=7.52 Hz); 7.99 (1H; d; J=7.4 Hz); 10.18 (1H; s).

Intermediate 34 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-methoxy-3-methyl-phenyl]methyl]carbamate

To a stirred and degassed solution of 2-formyl-4-methoxy-6-methylphenyltrifluoromethanesulfonate (3.01 g, 10.106 mmol) in dioxan (10 mL) wereadded DIPEA (3.53 mL, 20.212 mmol), Xanthphos (292 mg, 0.505 mmol),Pd₂(dba)₃ (231 mg, 0.253 mmol), methyl 2-sulfanylbenzoate (850 mg, 5.053mmol) and reaction mass was heated to 110° C. for 2 h. Reaction mixturewas filtered through celite pad, washed with ethyl acetate and filtrateevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 0-5% ethyl acetate and hexane to getmethyl 2-(2-formyl-4-methoxy-6-methyl-phenyl)sulfanylbenzoate (1.3 g,81%) as a off white solid.

To a stirred solution of methyl2-(2-formyl-4-methoxy-6-methyl-phenyl)sulfanylbenzoate (1.3 g, 4.109mmol) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (498 mg,4.109 mmol), Ti(OEt)₄(4.33 mL, 20.545 mmol) and reaction mass was heatedto 70° C. for 16 h. The reaction mass was quenched with saturated sodiumchloride solution, solid obtained was filtered through celite pad,washed with ethyl acetate. The separated organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure to getethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-methoxy-6-methyl-phenyl]sulfanylbenzoate(1.5 g crude) which was directly used for next step without furtherpurification. MS found: 434 (M+H).

To a stirred solution of ethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-methoxy-6-methyl-phenyl]sulfanylbenzoate(1.5 g, 3.459 mmol) in THF (15 mL) was added LiBH₄ (751 mg, 34.595 mmol)at 0° C. and reaction mass was heated to 50° C. for 4 h. The solvent wasevaporated and the reaction mass was quenched with NH₄Cl and extractedwith ethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to getN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.3 g crude) which was directly used for next step without furtherpurification. MS found: 394 (M+H).

To a stirred solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.3 g, 3.303 mmol) in MeOH (20 mL), was added 4M HCl in dioxane (10 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-4-methoxy-6-methyl-phenyl]sulfanylphenyl]methanol(1.1 g, crude) which was directly used for next step without furtherpurification. MS found: 290 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-4-methoxy-6-methyl-phenyl]sulfanylphenyl]methanol(1.1 g, 3.375 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (1.1 g, 3.375mmol) in CH₃CN (20 mL) at 25° C. and reaction mixture was stirred at 25°C. for 2 h. Then reaction mass was diluted with water and extracted withethyl acetate. The separated organic layer was washed with brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-30% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-3-methyl-phenyl]methyl]carbamate(1.2 g, 57%, 4 steps) as a off white solid. MS found: 511.9 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methoxy-3-methyl-phenyl]methyl]carbamate(1.2 g, 2.345 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂(4.07 g,46.907 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 5-20% ethyl acetate in hexane to9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-methoxy-3-methyl-phenyl]methyl]carbamate(800 mg, 67%) as an off white solid.

¹H-NMR: (400 MHz, DMSO-d6) δ 2.13 (3H; s); 3.79 (3H; s); 4.20-4.29 (5H;m); 6.42 (1H; d; J=8.0 Hz); 6.87 (1H; br s); 6.99 (1H; br s); 6.29-6.33(3H; m); 6.42 (3H; t; J=5.4 Hz); 7.69 (2H; d; J=7.40 Hz); 7.77-7.82 (1H;m); 7.89 (2H; d; J=7.52 Hz); 7.96 (1H; d; J=7.4 Hz); 10.21 (1H; s).

Intermediate 35 9H-fluoren-9-ylmethylN-[[5-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To an ice cooled solution of 2,5-Difluoro-benzaldehyde (5.21 g, 30.98mmol) and 2-Mercapto-benzoic acid methyl ester (4.0 g, 28.17 mmol) inDMF (20 mL, purged with argon for min) was added potassium carbonate(7.78 g, 56.33 mmol) and the reaction mixture was stirred at 0° C. for30 min. Then the reaction mixture was diluted with water (100 mL) andthe aq. phase was extracted with ethyl acetate (3×50 mL). Combinedorganic layer was washed with brine, dried over sodium sulfate andconcentrated under reduced pressure to get crude compound. The crudecompound thus obtained was purified by flash-chromatography (5% ethylacetate in hexane) to afford methyl2-(4-fluoro-2-formyl-phenyl)sulfanylbenzoate (2.4 g, 27%) as off whitesolid. MS found: 291.1 (M+H).

To a stirred solution of methyl2-(4-fluoro-2-formyl-phenyl)sulfanylbenzoate (2.9 g, 10 mmol) in dry THF(50 mL) under argon atmosphere was added titanium(IV) ethoxide (4.56 g,20 mmol) followed by tert-butyl sulphinamide (2.42 g, 20 mmol) and theresulting reaction mixture was heated to 70° C. for 4 h. Then thereaction mixture was cooled to room temperature, poured onto water (100mL), gelatinous white mass was filtered through celite. Celite bed waswashed thoroughly with ethyl acetate (50 mL). Organic layer wasseparated off. Aqueous layer was extracted with ethyl acetate (3×50 mL).Combined organic layer was dried over sodium sulfate and concentratedunder reduced pressure to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-fluoro-phenyl]sulfanylbenzoate(3.9 g, 99%) as white solid. MS found: 394.1 (M+H).

To an ice cooled suspension of LAH (1.15 g, 30.53 mmol) was added asolution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-fluoro-phenyl]sulfanylbenzoate(4.0 g, 10.17 mmol) in THF (50 mL) and the reaction mixture was stirredat 0° C. for 1 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with ethyl acetate andsaturated solution of sodium sulfate. Reaction mixture was filteredthrough celite and washed thoroughly with EtOAc (50 mL). Filtrate wasconcentrated to getN-[[5-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.6 g, 96%) as off white solid. MS found: 367.8 (M+H).

To an ice cooled solution ofN-[[5-fluoro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(3.0 g, 8.17 mmol) in DCM (150 mL) was added Dess-Martin periodinane(5.2 g, 12.26 mmol) portion-wise and the reaction mixture was stirred atroom temperature for 2 h under argon atmosphere. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with DCM (50 mL) and saturated sodium bicarbonate solution(50 mL). Organic layer was separated off and the aqueous layer wasextracted with DCM (2×50 mL). Combined organic layer was washed withsaturated sodium bicarbonate followed by brine. Organic layer was driedover Na₂SO₄, and evaporated under reduced pressure. Compound waspurified by flash-chromatography (50% EtOAc in hexane) to getN-[[5-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 67%) as white solid. MS found: 365.9 (M+H).

To an ice cooled solution ofN-[[5-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, crude) in dioxane (20 mL) was added 4M HCl in dioxane (30 mL)and the reaction mixture was stirred at room temperature for a period of2 h. Progress of the reaction was monitored by LCMS. Volatiles wereremoved under reduced pressure to get the crude compound which waswashed with diethyl ether (2×30 mL) and dried to get2-[2-(aminomethyl)-4-fluoro-phenyl]sulfanylbenzaldehyde (1.37 g, crude)as yellow solid.

To a stirred suspension of2-[2-(aminomethyl)-4-fluoro-phenyl]sulfanylbenzaldehyde (1.37 g, crude)in 5% sodium bicarbonate solution and acetonitrile (30 mL, 1:1) wasadded a solution of Fmoc-OSu (1.047 g, 3.05 mmol) in acetonitrile (15mL) and the reaction mixture was stirred at room temperature for 3 h.Progress of the reaction was monitored by TLC. After completion,volatiles were removed under reduced pressure and the crude reactionmixture was diluted with water (50 mL). The aq. phase was extracted withethyl acetate (50 mL×3). Combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by flash-chromatography (20% ethyl acetate in hexane) toafford desired compound which was further washed with n-pentane (5 mL)and dried to get 9H-fluoren-9-ylmethylN-[[5-fluoro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (0.6 g,23% over two steps) as white solid. LC-MS: 484.2 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.23-4.21 (3H, m), 4.33 (2H, d, J=6.9 Hz),6.63 (1H, d, J=8.0 Hz), 7.17 (1H, dd, J=10.0, 2.7 Hz), 7.35-7.24 (4H,m), 7.45-7.36 (3H, m), 7.48 (1H, t, J=6.3 Hz), 7.58 (1H, dd, J=8.5, 5.9Hz), 7.69 (2H, d, J=7.4 Hz), 7.89 (2H, d, J=7.8 Hz), 7.98 (1H, dd,J=7.5, 1.3 Hz), 10.19 (1H, s).

Intermediate 36 9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]carbamate

To an ice cooled solution of 3-Chloro-2-fluoro-5-methyl-benzaldehyde (4g, 23.25 mmol) and 2-Mercapto-benzoic acid methyl ester (3.91 g, 23.25mmol) in DMF (30 mL) under argon atmosphere was added potassiumcarbonate (6.4 g, 46.51 mmol) and the reaction was stirred at roomtemperature for 3 h. Progress of the reaction was monitored by TLC.After completion the reaction mixture was diluted with water (50 mL) andextracted with ethyl acetate (30 mL×3). Combined organic layer waswashed with brine (15 mL×3), dried over sodium sulfate and concentratedunder reduced pressure to get crude compound. The crude compound thusobtained was purified by flash-chromatography chromatography using 10%Ethyl acetate in hexane as eluent to get methyl2-(2-chloro-6-formyl-4-methyl-phenyl)sulfanylbenzoate (4.5 g, 61%) aspale yellow solid. LC-MS: 321.0 (M+H).

To a solution of methyl2-(2-chloro-6-formyl-4-methyl-phenyl)sulfanylbenzoate (3 g, 9.375 mmol)in anhydrous THF (100 mL) was added tert butylsulphinamide (1.7 g,14.062 mmol) followed by titanium (IV) ethoxide (3.2 g, 14.062 mmol) andthe reaction mixture was heated to 70° C. for 2 h under argonatmosphere. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was diluted with water (100 mL),filtered through celite and washed with ethyl acetate. Organic layer wasseparated off, washed with brine, dried over anhydrous sodium sulphateand concentrated under reduced pressure to get methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-4-methyl-phenyl]sulfanylbenzoate(3 g, 76%) as off white solid. LC-MS: 424.0 (M+H).

To an ice cooled suspension of LAH (0.807 g, 21.27 mmol) in THF (50 mL)was added methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-6-chloro-4-methyl-phenyl]sulfanylbenzoate(3 g, 7.092 mmol) in THF (30 mL) and the reaction mixture was stirredfor 30 min at 0° C. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate (5 mL) and filtered through celite. Residue was washed withethyl acetate (3×50 mL) and filtrate was concentrated to getN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.5 g, 90%) as white solid. LC-MS: 397.8 (M+H).

To an ice cooled solution ofN-[[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-5-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 5.04 mmol) in DCM (100 mL) was added Dess-Martin periodinane(2.34 g, 5.54 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was poured onto saturated sodiumbicarbonate solution and extracted with DCM (3×100 mL). Combined organiclayer was washed with sodium thiosulphate, dried over sodium sulphateand concentrated under reduced pressure to get the crude compound. Thecrude compound was purified by combiflash (30% EtOAc in hexane) toaffordN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.5 g, 76%) as off white solid. LC-MS: 396.1 (M+H).

To an ice cooled solution ofN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.5 g, 3.79 mmol) in dioxane (20 mL) was added 4M HCl in dioxane (2 mL)and the reaction mixture was stirred at room temperature for 1 h.Progress of the reaction was monitored by TLC. After completion,volatiles were evaporated under reduced pressure to obtain2-[2-(aminomethyl)-6-chloro-4-methyl-phenyl]sulfanylbenzaldehyde (1.2 g,crude) as off white solid. LC-MS: 292.1 (M+H).

To a suspension of2-[2-(aminomethyl)-6-chloro-4-methyl-phenyl]sulfanylbenzaldehyde (1.2 g,4.12 mmol) in 5% aqueous NaHCO₃ solution (5 mL) was added a solution ofFmoc-OSu (0.973 g, 2.88 mmol) in CH₃CN (20 mL) and the reaction mixturewas stirred at room temperature for 3 h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith ethyl acetate (50 mL) and organic layer was separated off. Organiclayer was washed with water followed by brine and dried over anhydroussodium sulfate. Organic layer was concentrated under reduced pressure toget the crude compound. The crude compound was purified byflash-chromatography (17% EtOAc in hexane) to afford9H-fluoren-9-ylmethylN-[[3-chloro-2-(2-formylphenyl)sulfanyl-5-methyl-phenyl]methyl]carbamate(1.0 g, 53%) as white solid. LC-MS: 513.9 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 2.37 (3H, s), 4.22-4.18 (1H, m), 4.32-4.28(4H, m), 6.48 (1H, d, J=8.0 Hz), 7.22 (1H, s), 7.38-7.31 (3H, m),7.46-7.40 (3H, m), 7.54 (1H, s), 7.69 (2H, d, J=7.4 Hz), 7.85 (1H, t,J=6.1 Hz), 7.89 (2H, d, J=7.5 Hz), 7.99 (1H, dd, J=7.52, 1.16 Hz), 10.19(1H, s).

Intermediate 37 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To an ice cooled solution of 3,5-Dichloro-2-fluoro-benzaldehyde (2.78 g,16.57 mmol) in DMF (20 mL, purged with argon for 10 min) under argonatmosphere were added 2-Mercapto-benzoic acid methyl ester (4.0 g, 20.72mmol) and potassium carbonate (8.59 g, 62.17 mmol) slowly and thereaction mixture was stirred at 0° C. for 30 min. Then the reactionmixture was diluted with water (100 mL) and the aq. phase was extractedwith ethyl acetate (50 mL×3). Combined organic layer was washed withbrine, dried over sodium sulfate and concentrated under reduced pressureto get crude compound. The crude compound thus obtained was purified byflash-chromatography (5% ethyl acetate in hexane) to afford methyl2-(2,4-dichloro-6-formyl-phenyl)sulfanylbenzoate (1.6 g, 23%) as offwhite solid. LC-MS: 339.8 (M+H).

To a stirred solution of methyl2-(2,4-dichloro-6-formyl-phenyl)sulfanylbenzoate (1.6 g, 4.69 mmol) indry THF (50 mL) under argon atmosphere was added titanium (IV) ethoxide(2.14 g, 9.38 mmol) followed by tert-butyl sulphinamide (1.137 g, 9.38mmol). The resulting reaction mixture was stirred at room temperaturefor 1 h and heated to 60° C. for 4 h. Then the reaction mixture wascooled to room temperature, poured onto water (100 mL) and filteredthrough celite bed. Celite bed was washed with ethyl acetate. Organiclayer was separated off and the aqueous layer was extracted with ethylacetate (50 mL×3). Combined organic layer was dried over sodium sulfateand concentrated under reduced pressure to get the crude compound. Thecrude compound thus obtained was purified by combiflash (25% ethylacetate in hexane) to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4,6-dichloro-phenyl]sulfanylbenzoate(2.0 g, 95%) as viscous oil. LC-MS: 443.9 (M+H).

To an ice cooled solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4,6-dichloro-phenyl]sulfanylbenzoate(2.0 g, 4.5 mmol) in THF (50 mL) under argon atmosphere was added LAH(0.512 g, 13.50 mmol) portion wise and the reaction mixture was stirredat 0° C. for 1 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with ethyl acetate andsaturated sodium sulfate solution. Then the reaction mixture wasfiltered through celite and washed with EtOAc. Filtrate was concentratedto getN-[[3,5-dichloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g, 95%) as off white solid. LC-MS: 417.7 (M+H).

To an ice cooled solution ofN-[[3,5-dichloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g, 4.30 mmol) in DCM (50 mL) was added Dess-Martin periodinane(2.24 g, 6.45 mmol) portion-wise and the reaction mixture was stirred atroom temperature for 2 h under argon atmosphere. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with DCM (50 mL) and saturated solution of sodiumbicarbonate (50 mL). Organic layer was separated off and the aqueouslayer was extracted with DCM (50 mL×2). Combined organic layer waswashed with sodium thiosulphate solution followed by brine. Volatileswere removed under reduced pressure to getN-[[3,5-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, crude) as viscous oil which was used as such in next stepwithout further purification. LC-MS: 416.0 (M+H).

To an ice cooled solution ofN-[[3,5-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, crude) in dioxane (20 mL) was added 4M HCl in dioxane (30 mL)and the reaction mixture was stirred at room temperature for a period of2 h. Progress of the reaction was monitored by LCMS. Volatiles wereremoved under reduced pressure to get the crude compound which waswashed with diethyl ether (30 mL×2) and dried well to get2-[2-(aminomethyl)-4,6-dichloro-phenyl]sulfanylbenzaldehyde (1.2 g,crude) as yellow solid. LC-MS: 312.1 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-4,6-dichloro-phenyl]sulfanylbenzaldehyde (1.2 g,crude) in 5% sodium bicarbonate solution and acetonitrile (30 mL, 1:1)was added a solution of Fmoc-OSu (1.047 g, 3.10 mmol) in acetonitrile(15 mL) and the reaction mixture was stirred at room temperature for 3h. Progress of the reaction was monitored by TLC. After completion,volatiles were removed under reduced pressure and the crude reactionmixture was diluted with water (50 mL). The aq. phase was extracted withethyl acetate (50 mL×3). Combined organic layer was washed with brine(50 mL×1), dried over anhydrous sodium sulfate and evaporated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by flash-chromatography (20% ethyl acetate in hexane) toafford desired compound which was further washed with n-pentane (5 mL)and dried to get 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate(0.75 g, 33% over three steps) as white solid. LC-MS: 533.7 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.22-4.19 (2H, m), 4.31-4.29 (3H, m), 6.51(1H, d, J=7.9 Hz), 7.37-7.31 (3H, m), 7.47-7.38 (4H, m), 7.68 (2H, d,J=7.4 Hz), 7.85 (1H, d, J=2.0 Hz), 7.89 (2H, d, J=7.5 Hz), 7.94 (1H, t,J=5.9 Hz), 8.01 (1H, d, J=7.4 Hz), 10.18 (1H, s).

Intermediate 38 9H-fluoren-9-ylmethylN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate

To a stirred solution of 5-chloro-2-fluoro-3-methylbenzoic acid (2.0 g,10.605 mmol) in THF (20 mL) was added LiAlH4 (21.0 ml, 21.0 mmol)drop-wise in ice cold condition and stirred at 25° C. for 30 min. It wasthen quenched with saturated Na₂SO₄ solution and extracted with ethylacetate, washed with brine and dried over Na₂SO₄ and concentrated undervacuum to get (5-chloro-2-fluoro-3-methyl-phenyl)methanol (1.8 g, crude)as a light yellow liquid. To a stirred solution of(5-chloro-2-fluoro-3-methyl-phenyl)methanol (1.8 g, 10.345 mmol) inDCM/THF (1:1.40 mL) was added MnO₂(8.993 g, 103.448 mmol) and reactionmass was stirred at 25° C. for 2 h. The reaction mass was filteredthrough celite pad, filtrate was evaporated under reduced pressure Thecrude thus obtained was purified by normal silica column using 2% ethylacetate in hexane to afford 5-chloro-2-fluoro-3-methyl-benzaldehyde (1.2g, 64.86%, 2 steps) as yellow liquid.

To a solution of 5-chloro-2-fluoro-3-methyl-benzaldehyde (1.0 g, 5.814mmol) in DMF (15.0 ml) were added Cs₂CO₃ (4.727 g, 14.535 mmol) andmethyl 2-sulfanylbenzoate (0.978 g, 5.814 mmol) and stirred at 60° C.for 2.5 h. Reaction mixture was diluted with water and extracted withEtOAc. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum to get thecompound which was purified by normal silica column using 0-2% ethylacetate in hexane to methyl2-(4-chloro-2-formyl-6-methyl-phenyl)sulfanylbenzoate (1.5 g, 80.43%) asa yellow solid. MS found: 321.2 (M+H).

To a stirred solution of methyl2-(4-chloro-2-formyl-6-methyl-phenyl)sulfanylbenzoate (1.5 g, 4.688mmol) in THF (25 mL) was added 2-methylpropane-2-sulfinamide (568 mg,4.688 mmol), Ti(OEt)₄ (4.914 ml, 23.438 mmol) and reaction mass washeated to 70° C. for 16 h. The reaction mass was quenched with saturatedsodium chloride solution, solid obtained was filtered through celitepad, washed with ethyl acetate. The separated organic layer was driedover anhydrous sodium sulfate and evaporated under reduced pressure toget ethyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-chloro-6-methyl-phenyl]sulfanylbenzoate(2.0 g, crude) which was directly used for next step without furtherpurification. MS found: 438.2 (M+H).

To a stirred solution of ethyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-chloro-6-methyl-phenyl]sulfanylbenzoate(2.0 g, 4.577 mmol) in THF (25 mL) was added LiBH₄ (0.997 g, 45.767mmol) at 0° C. and reaction mass was heated to 50° C. for 4 h. Thesolvent was evaporated and the reaction mass was quenched with NH₄Cl andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over sodium sulfate and evaporated underreduced pressure to getN-[[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g crude) which was directly used for next step without furtherpurification. MS found: 398.1 (M+H).

To a stirred solution ofN-[[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g, 4.534 mmol) in MeOH (40 mL), was added 4M HCl in dioxane (20 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-4-chloro-6-methyl-phenyl]sulfanylphenyl]methanol(1.6 g, crude) which was directly used for next step without furtherpurification. MS found: 293.8 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-4-chloro-6-methyl-phenyl]sulfanylphenyl]methanol(1.6 g, 5.461 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (1.841 g,5.461 mmol) in CH₃CN (20 mL) at 25° C. and reaction mixture was stirredat 25° C. for 2 h. Then reaction mass was diluted with water andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 5-30% ethyl acetate in hexane to9H-fluoren-9-ylmethylN-[[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]carbamate(1.4 g, 72%, 4 steps) as a off white solid. MS found: 516.2 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[5-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]carbamate(1.6 g, 3.107 mmol) in DCM/THF (1:1, 50 mL) was added MnO₂(5.401 g,62.136 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 5-20% ethyl acetate in hexane to9H-fluoren-9-ylmethylN-[[5-chloro-2-(2-formylphenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate(1.1 g, 68%) as a off white solid. MS found: 514.4 (M+H).

¹H-NMR: (400 MHz, DMSO-d6) δ 2.32 (3H; s); 4.19-4.29 (5H; m); 6.47 (1H;d; J=7.8 Hz); 6.29-6.37 (4H; m); 7.37-7.44 (3H; m); 7.51 (1H; br s);7.69 (2H; d; J=7.36 Hz); 7.87 (1H; m); 7.96 (2H; d; J=7.4 Hz); 7.99 (1H;d; J=7.6 Hz); 10.20 (1H; s).

Intermediate 39 9H-fluoren-9-ylmethylN-[[2-(4-fluoro-2-formyl-phenyl)sulfanylphenyl]methyl]carbamate

To an ice cooled solution of 2,5-Difluoro-benzaldehyde (5.21 g, 30.98mmol) and methyl 2-sulfanylbenzoate (4.0 g, 28.17 mmol) in DMF (20 mL,purged with argon for 10 min) was added potassium carbonate (7.78 g,56.33 mmol) and the reaction mixture was stirred at 0° C. for 30 min.Then the reaction mixture was diluted with water (100 mL) and the aq.phase was extracted with ethyl acetate (3×50 mL). Combined organic layerwas washed with brine, dried over sodium sulfate and concentrated underreduced pressure to get crude compound. The crude compound thus obtainedwas purified by flash-chromatography (5% ethyl acetate in hexane) toafford methyl 2-(4-fluoro-2-formyl-phenyl)sulfanylbenzoate (2.4 g, 27%)as off white solid. MS found: 291.1 (M+H).

A solution of methyl 2-(4-fluoro-2-formyl-phenyl)sulfanylbenzoate (i.e.3a) (2.0 g, 6.89 mmol), ethylene glycol (1.28 g, 20.69 mmol), p-TSA(0.131 g, 0.69 mmol) in toluene (100.0 mL) was heated to 140° C. for 6h. Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with water (100 mL) and organic layer wasseparated off. Aq. layer was further extracted with ethyl acetate (50mL×2). Combined organic layer was dried over anhydrous sodium sulfateand solvent distilled-off under reduced pressure to get methyl2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylbenzoate (1.70 g, 74%)as off white solid. LC-MS: 335.0 (M+NH4).

To an ice cooled suspension of LAH (0.454 g, 11.97 mmol) in THF (50 mL)was added methyl2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylbenzoate (1.6 g, 4.79mmol) in THF (30 mL) and the reaction mixture was stirred for 30 min at0° C. Progress of the reaction was monitored by TLC. After completion,the reaction mixture was quenched with saturated sodium sulphatesolution (5 mL) and filtered through celite. Residue was washed withethyl acetate (3×50 mL) and filtrate was concentrated under reducedpressure to get[2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylphenyl]methanol (1.4g, 96%) as white solid. MS found: 324.1 (M+18).

A suspension of[2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylphenyl]methanol (2.56g, 9.80 mmol), sodium azide (0.486 g, 7.84 mmol) in carbon tetrachloride(5.0 mL) and DMF (15.0 mL) was heated to 80° C. for 5 h. Progress of thereaction was monitored by TLC. Reaction mixture was diluted with water(20 mL) and compound was extracted with ethyl acetate (30 mL×2).Combined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to get crude compound which waspurified by silica gel column chromatography (30% ethyl acetate inhexane) to get2-[2-[2-(azidomethyl)phenyl]sulfanyl-5-fluoro-phenyl]-1,3-dioxolane (0.9g, 70%) as viscous oil. MS found: 349.1 (M+NH4).

To a solution of2-[2-[2-(azidomethyl)phenyl]sulfanyl-5-fluoro-phenyl]-1,3-dioxolane (0.9g, 2.71 mmol) in ethanol (20 mL) was added Pd—C (0.3 g) and the reactionmixture was agitated under hydrogen balloon pressure for 16 h. Then thereaction mixture was filtered through celite. Filtrate was concentratedunder reduced pressure to get[2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylphenyl]methanamine(0.800 g, 96%) as viscous oil. MS found: 305.9 (M+H).

To a suspension of[2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylphenyl]methanamine(0.800 g, 2.62 mmol) in 5% sodium bicarbonate (3 mL) was added Fmoc-OSu(0.619 g, 1.84 mmol) in acetonitrile (20 mL) and the reaction mixturewas stirred at ambient temperature for 3 h. Volatiles were removed underreduced pressure and the crude reaction mixture was diluted with water(50 mL). The aq. phase was extracted with ethyl acetate (50 mL×3).Combined organic layer was washed with brine (50 mL×1), dried overanhydrous sodium sulfate and evaporated under reduced pressure to getcrude compound. The crude compound thus obtained was purified byflash-chromatography (19% ethyl acetate in hexane) followed by washingwith diethyl ether:pentane (5 mL, 1:1) afforded 9H-fluoren-9-ylmethylN-[[2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylphenyl]methyl]carbamate(0.750 g, 54%) as white solid. MS found: 528.1 (M+H).

To a solution of 9H-fluoren-9-ylmethylN-[[2-[2-(1,3-dioxolan-2-yl)-4-fluoro-phenyl]sulfanylphenyl]methyl]carbamate(0.750 g, 1.42 mmol) in acetone (40 mL) was added 5N HCl (15 mL) and thereaction mixture was stirred at room temperature for 2 h. Volatiles wereremoved under reduced pressure and extracted with ethyl acetate (30mL×3). Combined organic layer was washed with 5% NaHCO₃ solution (50 mL)followed by water (50 mL). Organic layer was concentrated under reducedpressure to get crude compound which was purified byflash-chromatography (17% ethyl acetate in hexane) followed by washingwith diethyl ether-pentane (5 mL, 1:1) afforded 9H-fluoren-9-ylmethylN-[[2-(4-fluoro-2-formyl-phenyl)sulfanylphenyl]methyl]carbamate (0.550g, 80%) as off white solid. LC-MS: 483.8 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.26-4.19 (3H, m), 4.33 (2H, d, J=6.8 Hz),6.86 (1H, dd, J=8.8, 5.0 Hz), 7.48-7.31 (9H, m), 7.70 (2H, d, J=7.4 Hz),7.86-7.79 (2H, m), 7.89 (2H, d, J=7.5 Hz), 10.21 (1H, s).

Intermediate 40 9H-fluoren-9-ylmethylN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-3-methyl-phenyl]methyl]carbamate

A suspension of Na₂S.xH₂O (1.35 g, 17.374 mmol) and MgSO₄ (4 g) inN,N-dimethyl acetamide (40 mL) was stirred at 80° C. for a period of 30minutes under nitrogen atmosphere followed by the addition of2-Fluoro-3-methyl-benzaldehyde (2 g, 14.478 mmol) at the sametemperature. Stirring was continued for another 30 min at 80° C. Thereaction mixture was cooled to 0° C., acetic anhydride (1.9 mL, 20.269mmol) was added drop wise and the mixture was stirred at 0° C. foranother 30 min. The reaction mixture was diluted with ethyl acetate andwashed with water. The separated organic layer was washed with brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 0-5% ethyl acetate in hexane to getS-(2-formyl-6-methyl-phenyl) ethanethioate (830 mg, 29%) as an off whitesolid.

To the stirred solution of get S-(2-formyl-6-methyl-phenyl)ethanethioate (800 mg, 4.118 mmol) in THF (20 mL) were added 2-methyl2-propane sulfinamide (499 mg, 4.118 mmol) and Ti(OEt)₄ (4.349 mL,20.592 mmol) and heated to 70° C. for 45 min. Reaction mixture wasquenched with brine solution and extracted with ethyl acetate. Theseparated organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude thus obtained waspurified by normal silica column using 0-10% ethyl acetate in hexane togetS-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]ethanethioate(800 mg, 65%) as a colorless sticky liquid. MS found: 298.2 (M+H).

A solution ofS-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]ethanethioate(800 mg, 2.69 mmol) in THF (30 mL) was degassed with Argon for about 10minutes and then NaBH₄ (1017 mg, 26.896 mmol) was added portion-wiseunder cooling condition and stirred for 30 min. The reaction was thenquenched with acetone (10 mL) (degassed with argon) and stirred underthe cooling condition for 1 hr. Reaction mass was concentrated underreduced pressure and released in Argon to get2-methyl-N-[(3-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide(650 mg, crude) whish was directly used for next step without furtherpurification. MS found: 258.0 (M+H).

To a stirred solution of2-methyl-N-[(3-methyl-2-sulfanyl-phenyl)methyl]propane-2-sulfinamide(1.4 g, 5.439 mmol) and 2-Chloro-nicotinic acid tert-butyl ester (1.16g, 5.439 mmol) in acetonitrile (20 mL) was added K₂CO₃(1.5 g, 10.877mmol) and reaction mixture was heated to 70° C. for 4 h. Reactionmixture was diluted with ethyl acetate and washed with water. Theseparated organic layer was washed with brine solution, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by silica chromatography using 5-40%ethyl acetate in hexane to get tert-butyl2-[2-[(tert-butylsulfinylamino)methyl]-6-methyl-phenyl]sulfanylpyridine-3-carboxylate(700 mg, 30%, 2 steps) as a off white solid. MS found: 435 (M+H).

To a stirred solution of tert-butyl2-[2-[(tert-butylsulfinylamino)methyl]-6-methyl-phenyl]sulfanylpyridine-3-carboxylate(1.4 g, 3.665 mmol) in THF (20 mL) was added LiBH₄ (795 mg, 36.654 mmol)and reaction mixture was heated to 70° C. for 4 h. Reaction mixture wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over anhydrous and evaporated under reduced pressure.The crude thus obtained was purified by normal silica column using 5-60%ethyl acetate in hexane to getN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(800 mg, 57%) as a off white solid. MS found: 364.8 (M+H).

To a stirred solution ofN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(800 mg, 2.195 mmol) in MeOH (15 mL), was added 4M HCl/dioxane (30 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-6-methyl-phenyl]sulfanyl-3-pyridyl]methanol (650 mg,crude) as a off white solid. MS found: 260.9 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-methyl-phenyl]sulfanyl-3-pyridyl]methanol (650 mg,2.19 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (738 mg, 2.19 mmol) inCH₃CN (30 mL) at 25° C. and reaction was stirred at 25° C. for 2 h. Thenreaction mixture was diluted with water and extracted with ethylacetate. The separated organic layer was washed with brine solution,dried over sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by normal silica column using 5-30%ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-methyl-phenyl]methyl]carbamate(700 mg, 66%, 2 steps) as a off white solid. MS found: 482.9 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-methyl-phenyl]methyl]carbamate(700 mg, 1.45 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂ (2.52 g,29.009 mmol 1) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mixture was filtered through celite pad; filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby silica chromatography using 5-30% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-3-methyl-phenyl]methyl]carbamate(490 mg, 70%) as a off white solid. NMR complies.

¹H-NMR: (400 MHz, DMSO-d6) δ 2.32 (3H; s); 4.18-4.29 (5H; m); 7.16 (1H;d; J=7.48 Hz); 7.28-7.37 (5H; m); 7.40-7.44 (3H; m); 7.69 (2H; d; J=7.20Hz); 7.87 (1H; m); 7.96 (2H; d; J=7.48 Hz); 8.31 (1H; d; J=7.32 Hz);8.40 (1H; br d; J=4.04 Hz); 10.23 (1H; s).

Intermediate 41 9H-fluoren-9-ylmethylN-[(1S)-1-[3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]ethyl]carbamate

A solution of 1-(3-chloro-2-fluorophenyl)ethan-1-one (4 g, 23.176 mmol),(2-sulfanylphenyl)methanol (3.25 g, 23.176 mmol), 63% aq. NaOH (1.2 mL)and HMPA (40 mL) was heated to 100° C. for 5 h. The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude material obtained was purified bysilica chromatography (100-200 mesh) using 0-20% EtOAc in hexane to get1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethanone (4 g,59%) as a colourless sticky liquid.

To the stirred solution of1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethanone (4 g,13.662 mmol) in THF (40 mL) were added (S) 2-methyl 2-propanesulfinamide (1.65 g, 13.662 mmol) and Ti(OEt)₄ (14.4 mL, 68.308 mmol)and heated to 70° C. for 16 h. The reaction mixture was quenched withbrine solution and extracted with ethyl acetate. The separated organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude material obtained was purified by normalsilica column using 0-30% ethyl acetate in hexane to affordN-[1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide(3.2 g, 59%) as a yellow solid. MS found: 395.9 (M+H).

To a stirred solution ofN-[1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide(600 mg, 1.515 mmol) in THF (20 mL) was added L-selectride (7.5 mL, 7.5mmol) at 25° C. and stirred at the same temperature for 16 h. Then thereaction mixture was quenched with saturated NH₄Cl solution andextracted with ethyl acetate, dried over Na₂SO₄ and concentrated undervacuum to getN-[(1S)-1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]-2-methyl-propane-2-sulfinamide(600 mg, crude) as off white sticky solid. MS found: 398.0 (M+H).

To a stirred solution ofN-[(1S)-1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]-2-methyl-propane-2-sulfinamide(500 mg, 1.256 mmol) in MeOH (20 mL), was added 4M HCl/dioxane (10 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-[(1S)-1-aminoethyl]-6-chloro-phenyl]sulfanylphenyl]methanol (400mg, crude) as a off white solid. MS found: 294.0 (M+H).

To a stirred suspension of[2-[2-[(1S)-1-aminoethyl]-6-chloro-phenyl]sulfanylphenyl]methanol (480mg, 1.453 mmol) in 5% NaHCO₃(10 mL) was added Fmoc OSU (489 mg, 1.453mmol) in CH₃CN (10 mL) at 25° C. and reaction was stirred at 25° C. for2 h. Then reaction mixture was diluted with water and extracted withethyl acetate. The separated organic layers were washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure. The crude thus obtained was purified by normal silica columnusing 5-30% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[(1S)-1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]carbamate(420 mg, 54%, 3 steps) as a off white solid. MS found: 516.2 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[(1S)-1-[3-chloro-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]ethyl]carbamate(420 mg, 0.814 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂(1.414 g,16.277 mmol) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad; filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[(1S)-1-[3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]ethyl]carbamate(350 mg, 83%) as a off white solid. ¹H-NMR: (400 MHz, DMSO-d6) δ 1.26(3H; d; J=6.76 Hz); 4.18-4.23 (3H; m); 5.23 (1H; m); 6.59 (1H; d; J=8.04Hz); 7.31-7.43 (5H; m); 7.58 (2H; m); 7.68 (2H; m); 7.90 (2H; d; J=7.4Hz); 7.96 (1H; d; J=7.4 Hz); 8.03 (1H; d; J=7.36 Hz); 10.21 (1H; s).

Intermediate 42 9H-fluoren-9-ylmethylN-[[3-chloro-2-(4-fluoro-2-formyl-phenyl)sulfanyl-phenyl]methyl]carbamate

To a stirred solution of 4-fluoro-3-formyl-benzoic acid (2.5 g, 14.535mmol) in THF (20 mL), was added tert-butyl2,2,2-trichloroethanecarboximidate (9.112 mL, 50.872 mmol) followed byslow addition of BF₃.OEt₂ (1.54 mL, 14.535 mmol) at 0° C. and stirred atroom temperature for 2 h. After completion of reaction, reaction mixturewas quenched with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to get crude materialwhich was purified by normal silica column using 1% ethyl acetate inhexane to get tert-butyl 5-fluoro-2-sulfanyl-benzoate (1.7 g, 51%) asyellow solid.

To a stirred solution of tert-butyl 5-fluoro-2-sulfanylbenzoate (2 g,8.761 mmol) and 3-chloro-2-fluoro-benzaldehyde (1.38 g, 8.761 mmol) inDMF (12 mL) was added K₂CO₃ (2.4 g, 17.522 mmol) and reaction mass wasstirred at 25° C. for 1 h. Reaction mixture was diluted with ethylacetate and washed with water. The separated organic layer was washedwith brine solution, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 0-2% ethyl acetate in hexane to get tert-butyl2-(2-chloro-6-formyl-phenyl)sulfanyl-5-fluoro-benzoate (1.8 g, 56%) as ayellow solid.

To the stirred solution of tert-butyl2-(2-chloro-6-formyl-phenyl)sulfanyl-5-fluoro-benzoate (1.8 g, 4.907mmol) in THF (20 mL) were added 2-methyl 2-propane sulfinamide (595 mg,4.907 mmol) and Ti(OEt)₄ (5.18 mL, 24.534 mmol) and heated to 70° C. for1 h. The reaction mixture was quenched with brine solution and extractedwith ethyl acetate. The separated organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum to affordtert-butyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-chloro-phenyl]sulfanyl-5-fluoro-benzoate(2 g, crude) as a yellow solid. MS found: 470.2 (M+H).

To a stirred solution of tert-butyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-chloro-phenyl]sulfanyl-5-fluoro-benzoate(2 g, 4.255 mmol) in THF (30 mL) was added LiBH₄ (923 mg, 42.55 mmol)and reaction mixture was heated to 70° C. for 8 h. The reaction mixturewas quenched with saturated ammonium chloride solution and extractedwith ethyl acetate. The separated organic layer was washed with water,brine solution, dried over anhydrous sodium sulfate and evaporated underreduced pressure to getN-[[3-chloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, crude) which was directly used for next step. MS found: 401.7(M+H).

To a stirred solution ofN-[[3-chloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 4.2229 mmol) in MeOH (24 mL), was added 4M HCl/dioxane (12 mL)at 0° C. and reaction mixture was stirred at 25° C. for 20 min. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-6-chloro-phenyl]sulfanyl-5-fluoro-phenyl]methanol(1.4 g, crude) as a sticky liquid. MS found: 298.1 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-phenyl]sulfanyl-5-fluoro-phenyl]methanol(1.4 g, 4.188 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (1.41 g,4.188 mmol) in CH₃CN (20 mL) at 25° C. and reaction was stirred at 25°C. for 2 h. Then reaction mass was diluted with water and extracted withethyl acetate. The separated organic layers were washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(2 g, crude) which was directly used for next step without furtherpurification. MS found: 520.1 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate(1 g, 1.923 mmol) in DCM/THF (1:1, mL) was added MnO₂(3.3 g, 38.459mmol) and reaction mass was stirred at 25° C. for 2 h. The reactionmixture was filtered through celite pad; filtrate was evaporated underreduced pressure.

The crude thus obtained was purified by normal silica column using 5-40%ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-(4-fluoro-2-formyl-phenyl)sulfanyl-phenyl]methyl]carbamate(420 mg, 42%, 5 steps) as a off white solid. ¹H-NMR: (400 MHz, DMSO-d6)δ 4.12-4.33 (5H; m); 6.55-6.59 (1H; m); 7.30-7.41 (5H; m); 7.56 (1H; t;J=7.72 Hz); 7.61-7.66 (3H; m); 7.84-7.90 (4H; m); 10.19 (1H; s).

Intermediate 43 9H-fluoren-9-ylmethylN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-5-methoxy-phenyl]methyl]carbamate

A suspension of Na₂S.xH₂O (1.2 g, 15.57 mmol) and MgSO₄(4 g) inN,N-dimethyl acetamide (40 mL) was stirred at 90° C. for a period of 90minutes under nitrogen atmosphere followed by the addition of2-Fluoro-5-methoxy-benzaldehyde (2 g, 12.975 mmol) at the sametemperature. Stirring was continued for another 5 h at 90° C. Thereaction mixture was cooled to 0° C., acetic anhydride (12.2 mL, 129.752mmol) was added drop-wise and the mixture was stirred at 0° C. for 30min and 25° C. for 16 h. The reaction mixture was diluted with ethylacetate and washed with water. The separated organic layer was washedwith brine solution, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to get S-(2-formyl-4-methoxy-phenyl)ethanethioate (2 g, crude) which was directly used for next step withoutfurther purification. MS found: 211.0 (M+H).

To the stirred solution of S-(2-formyl-4-methoxy-phenyl) (2.8 g, 13.333mmol) in THF (20 mL) were added 2-methyl 2-propane sulfinamide (1.616 g,13.333 mmol) and Ti(OEt)₄ (2.795 ml, 13.333 mmol) and heated to 70° C.for 45 min. The reaction mixture was quenched with brine solution andextracted with ethyl acetate. The separated organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude thus obtained was purified by normal silica column using 0-10%ethyl acetate in hexane to getS-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-methoxy-phenyl]ethanethioate(980 mg, 17%, 2 steps) as a colorless sticky liquid. MS found: 313.8(M+H).

A solution ofS-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-methoxy-phenyl]ethanethioate(980 mg, 3.131 mmol) in THF (15 mL) was degassed with argon for about 10minutes and then NaBH₄ (1.184 g, 31.31 mmol) was added portion-wiseunder cooling condition and stirred for 30 min at 0° C. The reaction wasthen quenched with acetone (10 mL) (degassed with argon) and stirredunder the cooling condition for 1 hr. Reaction mass was concentratedunder reduced pressure and released in Argon to getN-[(5-methoxy-2-sulfanyl-phenyl)methyl]-2-methyl-propane-2-sulfinamide(855 mg, crude) whish was directly used for next step without furtherpurification.

To a stirred solution ofN-[(5-methoxy-2-sulfanyl-phenyl)methyl]-2-methyl-propane-2-sulfinamide(854 mg, 3.128 mmol) and 2-Chloro-nicotinic acid tert-butyl ester(668.497 mg, 3.128 mmol) in acetonitrile (15 mL) was added K₂CO₃(1.08 g,7.821 mmol) and reaction mass was heated to 70° C. for 4 h. Reactionmass was diluted with ethyl acetate and washed with water. The separatedorganic layer was washed with brine solution, dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude thusobtained was purified by normal silica column using 10-60% ethyl acetatein hexane to get tert-butyl2-[2-[(tert-butylsulfinylamino)methyl]-4-methoxy-phenyl]sulfanylpyridine-3-carboxylate(420 mg, 30%, 2 steps) as a white sticky solid. MS found: 450.8 (M+H).

To a stirred solution of tert-butyl2-[2-[(tert-butylsulfinylamino)methyl]-4-methoxy-phenyl]sulfanylpyridine-3-carboxylate(470 mg, 1.044 mmol) in THF (12 mL) was added LiBH₄ (227.48 mg, 10.44mmol) and reaction mass was heated to 70° C. for 4 h. Reaction mass wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over anhydrous and evaporated under reduced pressure togetN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-methoxy-phenyl]methyl]-2-methyl-propane-2-sulfinamide(370 mg, crude) as a off white sticky solid. MS found: 380.9 (M+H).

To a stirred solution ofN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-methoxy-phenyl]methyl]-2-methyl-propane-2-sulfinamide(370.0 mg, 0.974 mmol) in MeOH (10 mL), was added 4M HCl/dioxane (5 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-4-methoxy-phenyl]sulfanyl-3-pyridyl]methanol (300mg, crude) as an off white solid. MS found: 276.9 (M+H).

To a stirred suspension[2-[2-(aminomethyl)-4-methoxy-phenyl]sulfanyl-3-pyridyl]methanol (300mg, 1.087 mmol) in 5% NaHCO₃(5 mL) was added Fmoc OSU (366.522 mg, 1.087mmol) in CH₃CN (5 mL) at 25° C. and reaction was stirred at 25° C. for 2h. Then reaction mass was diluted with water and extracted with ethylacetate. The separated organic layer was washed with brine solution,dried over sodium sulfate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-methoxy-phenyl]methyl]carbamate(350 mg, crude) as a off white solid. MS found: 498.8 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-methoxy-phenyl]methyl]carbamate(350 mg, 0.703 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂(610.954 mg,7.028 mmol) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad; filtrate was evaporatedunder reduced pressure. The crude material obtained was purified bynormal silica column using 5-30% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[2-[(3-formyl-2-pyridyl)sulfanyl]-5-methoxy-phenyl]methyl]carbamate(250 mg, 48%, 4 steps) as a off white solid.

¹H-NMR: (400 MHz, DMSO-d6) δ 3.79 (3H; s); 4.17-4.21 (3H; m); 4.26-4.28(2H; m); 6.90-6.92 (1H; m); 6.96 (1H; m); 7.30-7.36 (3H; m); 7.39-7.44(3H; m); 7.69 (2H; d; J=7.48 Hz); 7.84 (1H; m); 7.90 (2H; d; J=7.4 Hz);8.30 (1H; d; J=7.4 Hz); 8.4 (1H; d; J=3.56 Hz); 10.19 (1H; s).

Intermediate 44 9H-fluoren-9-ylmethylN-[[2-(4-fluoro-2-formyl-phenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate

To a stirred solution of tert-butyl 5-fluoro-2-sulfanylbenzoate (1.2 g,5.256 mmol) and 2-fluoro-3-methyl-benzaldehyde (726 mg, 5.256 mmol) inDMF (12 mL) was added Cs₂CO₃ (3.4 g, 10.513 mmol) and reaction mass washeated to 70° C. for 3 h. Reaction mixture was diluted with ethylacetate and washed with water. The separated organic layer was washedwith brine solution, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude material obtained was purified bysilica chromatography using 0-2% ethyl acetate in hexane to gettert-butyl 5-fluoro-2-(2-formyl-6-methyl-phenyl)sulfanyl-benzoate (600mg, 33%) as a colorless sticky liquid.

To the stirred solution of tert-butyl5-fluoro-2-(2-formyl-6-methyl-phenyl)sulfanyl-benzoate (1.2 g, 3.464mmol) in THF (20 mL) were added 2-methyl 2-propane sulfinamide (420 mg,3.464 mmol) and Ti(OEt)₄ (3.65 mL, 17.32 mmol) and heated to 70° C. for1 h. Reaction mixture was quenched with brine solution and extractedwith ethyl acetate. The separated organic layer was dried over anhydroussodium sulfate and concentrated under vacuum to tert-butyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]sulfanyl-5-fluoro-benzoate(1.3 g, crude) as a yellow solid. MS found: 449.7 (M+H).

To a stirred solution of tert-butyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-methyl-phenyl]sulfanyl-5-fluoro-benzoate(1.3 g, 2.891 mmol) in THF (20 mL) was added LiBH₄ (627 mg, 28.914 mmol)and reaction mass was heated to 70° C. for 8 h. Reaction mixture wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-50% EA/Hex to getN-[[2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1 g, 75%, 2 steps) as a off white solid. MS found: 382.0 (M+H).

To a stirred solution ofN-[[2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1 g, 2.62 mmol) in MeOH (10 mL), was added 4M HCl/dioxane (5 mL) at 0°C. and reaction mixture was stirred at 25° C. for 1 h. After completionof reaction, reaction mixture was concentrated under reduced pressure toget[2-[2-(aminomethyl)-6-methyl-phenyl]sulfanyl-5-fluoro-phenyl]methanol(800 mg, crude) as a sticky liquid. MS found: 277.9 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-methyl-phenyl]sulfanyl-5-fluoro-phenyl]methanol(800 mg, 2.549 mmol) in 5% NaHCO₃(10 mL) was added Fmoc OSU (859 mg,2.549 mmol) in CH₃CN (10 mL) at 25° C. and reaction was stirred at 25°C. for 2 h. Then reaction mass was diluted with water and extracted withethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure. The crude material obtained was purified by silicachromatography using 5-30% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]carbamate(800 mg, 61%, 2 steps) as a off white solid. MS found: 500.1 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[2-[4-fluoro-2-(hydroxymethyl)phenyl]sulfanyl-3-methyl-phenyl]methyl]carbamate(800 mg, 1.661 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂(2.88 g,33.221 mmol) and reaction mixture was stirred at 25° C. for 2 h. Thereaction mixture was filtered through celite pad; filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby silica chromatography using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[2-(4-fluoro-2-formyl-phenyl)sulfanyl-3-methyl-phenyl]methyl]carbamate(510 mg, 61%) as a off white solid. MS found: 498.1 (M+H).

¹H-NMR: (400 MHz, DMSO-d6) δ 2.2 (3H; s); 4.19-4.21 (1H; m); 4.23-4.30(4H; m); 6.45 (1H; m); 7.23 (1H; br s; J=6.88 Hz); 7.32-7.45 (7H; m);7.67 (1H; d; J=7.04 Hz); 7.78-7.90 (4H; m); 10.20 (1H; s).

Intermediate 45 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-5-(trifluoromethyl)phenyl]methyl]carbamate

To a stirred solution of 2-mercapto-nicotinic acid methyl ester (1.23 g,7.283 mmol), in DMF (15 mL) was added KOtBu (817 mg, 7.283 mmol) andreaction mass was stirred at 25° C. for 30 min. Then3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (1.5 g, 6.621 mmol) wasadded to the reaction mass and it was heated to 80° C. for 1 h. Thereaction mixture was quenched with water and extracted with ethylacetate. The separated organic layer was washed with brine solution,dried over anhydrous sodium sulfate and evaporated under reducedpressure to get methyl2-[2-chloro-6-formyl-4-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(2.3 g, crude) which was directly used for next step without furtherpurification. MS found: 375.5 (M+H).

To a stirred solution of methyl2-[2-chloro-6-formyl-4-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(2.3 g, 6.121 mmol) in THF (20 mL) were added2-methylpropane-2-sulfinamide (742 mg, 6.121 mmol) and Ti(OEt)₄ (6.4 mL,30.605 mmol) and heated to 70° C. for 1 h. Reaction mixture was quenchedwith brine solution and extracted with ethyl acetate. The separatedorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum to afford ethyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-chloro-4-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(2.8 g, crude) which was directly used for next step without furtherpurification. MS found: 492.6 (M+H).

To a stirred solution of ethyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-6-chloro-4-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(2.8 g, 5.68 mmol) in THF (20 mL) was added LAH (1M in THF, 11.36 mL,11.36 mmol) at 0° C. and reaction mass was stirred at 25° C. for 2 h.The reaction mixture was quenched with saturated sodium sulfate solutionand extracted with ethyl acetate. The separated organic layers werewashed with water, brine solution, dried over anhydrous sodium sulfateand evaporated under reduced pressure. The crude material obtained waspurified by silica chromatography using 10-60% ethyl acetate in hexaneto getN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 47%, 3 steps) as an off white solid. MS found: 452.8 (M+H).

To a stirred solution ofN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, 3.091 mmol) in MeOH (40 mL), was added 4M HCl in dioxane (20 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, the mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]methanol(1 g, crude) as off white solid which was directly used for next step.MS found: 348.7 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]methanol(1 g, 2.596 mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (875 mg, 2.596mmol) in CH₃CN (20 mL) at 25° C. and reaction mixture was stirred at 25°C. for 2 h. Then reaction mixture was diluted with water and extractedwith ethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to get the crude which was purified by normal silica columnusing 5-30% ethyl acetate in hexane to 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-(trifluoromethyl)phenyl]methyl]carbamate(1.1 g, 62%, 2 steps) as off-white solid. MS found: 570.8 (M+H).

To a stirred solution ofN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-(trifluoromethyl)phenyl]methyl]carbamate(1.1 g, 1.926 mmol) in DCM/THF (1:1, 40 mL) was added MnO₂(3.34 g,38.528 mmol)) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure to get the crude which was purified by normalsilica column using 5-20% ethyl acetate in hexane to afford the9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-5-(trifluoromethyl)phenyl]methyl]carbamateas off-white solid (650 mg, 59%).

¹H-NMR: (400 MHz, DMSO-d6) δ 4.20-4.21 (1H; m); 4.22-4.28 (2H; m);4.34-4.35 (2H; m); 7.28-7.32 (2H; m); 7.39-7.43 (3H; m); 7.66-7.68 (3H;m); 7.89 (2H; d; J=7.4 Hz); 7.96-7.97 (1H; m); 7.99 (1H; br s);8.39-8.43 (2H; m); 10.19 (1H; s).

Intermediate 46 9H-fluoren-9-ylmethylN-[[3-(2-formylphenyl)sulfanyl-4-pyridyl]methyl]carbamate

To a stirred solution of 2-chloro-pyridine-3-carbaldehyde (2.0 g, 14.124mmol) and methyl thio salicylate (2.376 g, 14.124 mmol) in DMF (20 mL)was added Cs₂CO₃ (9.181 g, 28.249 mmol) and reaction mass was heated to70° C. for 2 h. The reaction mixture was diluted with ethyl acetate andwashed with water. The separated organic layers were washed with brinesolution, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by silicachromatography using 10-50% ethyl acetate in hexane to get methyl2-[(3-formyl-2-pyridyl)sulfanyl]benzoate (3 g, 77%) as a yellow solid.

To the stirred solution of methyl2-[(3-formyl-2-pyridyl)sulfanyl]benzoate (3.02 g, 11.062 mmol) in THF(25 mL) were added 2-methyl 2-propane sulfinamide (1.341 g, 11.062 mmol)and Ti(OEt)₄ (11.597 mL, 55.311 mmol) and heated to 70° C. for 90 min.The reaction mixture was quenched with brine solution and extracted withethyl acetate. The separated organic layers were dried over anhydroussodium sulfate and concentrated under vacuum to afford ethyl2-[[3-[(Z)-tert-butylsulfinyliminomethyl]-2-pyridyl]sulfanyl]benzoate(3.5 g, crude) as a yellow solid. MS found: 390.7 (M+H).

To a stirred solution of ethyl2-[[3-[(Z)-tert-butylsulfinyliminomethyl]-2-pyridyl]sulfanyl]benzoate(3.5 g, 8.974 mmol) in THF (25 mL) was added LiBH₄ (1.955 g, 89.744mmol) and reaction mixture was heated to 70° C. for 3 h. The reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate. The separated organic layers were washedwith water, brine solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure to getN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-3-pyridyl]methyl]-2-methyl-propane-2-sulfinamide(3 g, crude) as a off white solid. MS found: 350.8 (M+H).

To a stirred solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-3-pyridyl]methyl]-2-methyl-propane-2-sulfinamide(3.0 g, 8.571 mmol) in MeOH (30 mL), was added 4M HCl/dioxane (15 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, the mixture was concentrated under reducedpressure to get [2-[[3-(aminomethyl)-2-pyridyl]sulfanyl]phenyl]methanol(2.5 g, crude) as a sticky liquid. MS found: 247.1 (M+H).

To a stirred suspension of[2-[[3-(aminomethyl)-2-pyridyl]sulfanyl]phenyl]methanol (2.5 g, 10.163mmol) in 5% NaHCO₃(20 mL) was added Fmoc OSU (3.427 g, 10.163 mmol) inCH₃CN (20 mL) at 25° C. and reaction was stirred at 25° C. for 3 h. Thenreaction mixture was diluted with water and extracted with ethylacetate. The separated organic layers were washed with brine solution,dried over sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by silica chromatography using 5-50%ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-3-pyridyl]methyl]carbamate (1.6g, 31%, 4 steps) as a off a white solid. MS found: 468.8 (M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-3-pyridyl]methyl]carbamate (2.0g, 4.274 mmol) in DCM/THF (1:1, 50 mL) was added MnO₂(7.43 g, 85.47mmol) and reaction mixture was stirred at 25° C. for 2 h. The reactionmixture was filtered through celite pad; filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 10-70% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3-(2-formylphenyl)sulfanyl-4-pyridyl]methyl]carbamate (600 mg, 28%,3 steps) as an off white solid.

¹H-NMR: (400 MHz, DMSO-d6) δ 4.11-4.24 (3H; m); 4.37-4.38 (2H; m); 6.62(2H; d; J=7.52 Hz); 7.25 (1H; m); 7.32-7.35 (3H; m); 7.42-7.47 (3H; m);7.47-7.49 (1H; m); 7.70 (2H; d; J=7.16 Hz); 7.92 (2H; br d; J=6.88 Hz);8.01 (1H; br d; J=6.92 Hz); 8.5 (1H; br s); 8.66 (1H; d; J=4.76 Hz);10.21 (1H; s).

Intermediate 47 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a stirred solution of 2-mercapto-nicotinic acid (2.44 g, 15.755mmol), in DMF (30 mL) was added KOtBu (3.2 g, 28.645 mmol) and reactionmixture was stirred at 25° C. for 30 min. Then2,3,5-trichloro-benzaldehyde (3 g, 14.323 mmol) was added to thereaction mass and it was heated to 80° C. for 4 h. Then K₂CO₃(5.93 g,42.968 mmol) was added followed by addition of MeI (2.67 mL, 42.968mmol) and reaction mass was stirred at 25° C. for 16 h. The reactionmixture was quenched with water and extracted with ethyl acetate. Theseparated organic layer was washed with brine solution, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by normal silica column using 5-15%ethyl acetate in hexane to get methyl2-(2,4-dichloro-6-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.3 g,46%) as a yellow solid. MS found: 341.8 (M+H).

To a stirred solution of methyl2-(2,4-dichloro-6-formyl-phenyl)sulfanylpyridine-3-carboxylate (2.3 g,6.721 mmol) in THF (20 mL) were added 2-methylpropane-2-sulfinamide (815mg, 6.721 mmol) and Ti(OEt)₄ (7.09 mL, 33.606 mmol) and reaction massheated to 70° C. for 1 h. Reaction mixture was quenched with brinesolution and extracted with ethyl acetate. The separated organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford ethyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4,6-dichloro-phenyl]sulfanylpyridine-3-carboxylate(2.6 g, crude) which was directly used for next step without furtherpurification. MS found: 458.7 (M+H).

To a stirred solution of methyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4,6-dichloro-phenyl]sulfanylpyridine-3-carboxylate(2.6 g, 5.659 mmol) in THF (25 mL) was added LAH (1M in THF, 11.31 mL,11.31 mmol) at 0° C. and reaction mass was stirred at 25° C. for 2 h.Reaction mixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate.

The separated organic layer was washed with water, brine solution, driedover anhydrous sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by normal silica column using 10-60%ethyl acetate in hexane to getN-[[3,5-dichloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.5 g, 53%, 2 steps) as off white solid. MS found: 418.8 (M+H).

To a stirred solution ofN-[[3,5-dichloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.9 g, 11.429 mmol) in MeOH (20 mL), was added 4M HCl in dioxane (12mL) at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, the mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-4,6-dichloro-phenyl]sulfanyl-3-pyridyl]methanol (1.9g, crude) as off white solid which was directly used for next step. MSfound: 315.1 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-4,6-dichloro-phenyl]sulfanyl-3-pyridyl]methanol (1.9g, 6.051 mmol) in 5% NaHCO₃(25 mL) was added Fmoc OSU (2.04 g, 6.051mmol) in CH₃CN (25 mL) at 25° C. and reaction mass was stirred at 25° C.for 3 h. Then reaction mass was diluted with water and extracted withethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to get 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(2.5 g, crude) which was directly used for next step. MS found: 537.0(M+H).

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(2.5 g, 4.664 mmol) in DCM/THF (1:1, 70 mL) was added MnO₂(4.055 g,46.642 mmol) and reaction mass was stirred at 25° C. for 3 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure to get the crude which was purified by silicachromatography using 5-40% ethyl acetate in hexane to afford9H-fluoren-9-ylmethylN-[[3,5-dichloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamateas off-white solid (1.7 g, 69%, 3 steps).

¹H-NMR: (400 MHz, DMSO-d6) δ 4.21-4.30 (5H; m); 7.25-7.43 (6H; m); 7.67(2H; d; J=7.26 Hz); 7.79 (1H; s); 7.90 (2H; br d; J=7.16 Hz); 8.36 (1;br d; J=7.36 Hz); 8.40 (1H; br s); 10.18 (1H; s).

Intermediate 48 9H-fluoren-9-ylmethylN-[[6-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-3-(trifluoromethyl)phenyl]methyl]carbamate

To a stirred solution of ethyl 2-mercapto-nicotinic acid (2.116 g,13.636 mmol), in DMF (30 mL) was added KOtBu (2.782 g, 24.793 mmol) andreaction mass was stirred at 25° C. for 30 min. Then2,6-dichloro-3-trifluoromethyl-benzaldehyde (3.0 g, 12.397 mmol) wasadded to the reaction mass and it was heated to 80° C. for 4 h. ThenK₂CO₃(5.14 g, 37.19 mmol) was added followed by addition of MeI (2.325mL, 39.19 mmol) and reaction mixture was stirred at 25° C. for 16 h. Thereaction mixture was quenched with water and extracted with ethylacetate. The separated organic layer was washed with brine solution,dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude thus obtained was purified by silica chromatographyusing 0-10% methyl acetate in hexane to get methyl2-[3-chloro-2-formyl-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(3.3 g, 71%) as a yellow solid.

To a stirred solution of methyl acetate in hexane to get methyl2-[3-chloro-2-formyl-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(3.5 g, 9.314 mmol) in THF (30 mL) were added2-methylpropane-2-sulfinamide (1.12 g, 9.314 mmol) and Ti(OEt)₄ (9.837mL, 46.572 mmol) and reaction mass heated to 70° C. for 1 h. Thereaction mixture was quenched with brine solution and extracted withethyl acetate. The separated organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-chloro-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(4.2 g, crude) which was directly used for next step without furtherpurification. MS found: 492.5 (M+H).

To a stirred solution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-chloro-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate(4.2 g, 8.52 mmol) in THF (40 mL) was added LAH (1M in THF, 17.04 mL,17.04 mmol) at 0° C. and reaction mixture was stirred at 25° C. for 2 h.The reaction mixture was quenched with saturated sodium sulfate solutionand extracted with ethyl acetate. The separated organic layer was washedwith water, brine solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 10-60% ethyl acetate in hexane to getN-[[6-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.7 g, 52%, 2 steps) as off white solid. MS found: 452.9 (M+H).

To a stirred solution ofN-[[6-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.5 g, 3.319 mmol) in MeOH (20 mL), was added 4M HCl in dioxane (10 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to get[2-[2-(aminomethyl)-3-chloro-6-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]methanol(1.5 g, crude) as a yellow sticky solid which was directly used for nextstep. MS found: 348.7 (M+H).

To a stirred solution of[2-[2-(aminomethyl)-3-chloro-6-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]methanol(2.0 g, 3.509 mmol) in DCM/THF (1:1, 60 mL) was added MnO₂(3.05 g,35.088 mmol) and reaction mass was stirred at 25° C. for 3 h. Thereaction mass was filtered through celite pad, filtrate was evaporatedunder reduced pressure to get the crude material which was purified bysilica chromatography using 5-40% ethyl acetate in hexane to afford9H-fluoren-9-ylmethylN-[[6-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-3-methyl-phenyl]methyl]carbamateas off-white solid (1.1 g, 58%, 3 steps).

¹H-NMR: (400 MHz, DMSO-d6) δ 4.16-4.22 (3H; m); 4.32-4.45 (2H; m); 7.32(2H; br t; J=7.28 Hz); 7.40 (3H; br t; J=7.28 Hz); 7.60 (1H; m); 7.67(2H; br d; J=7.24 Hz); 7.73 (2H; br d; J=7.96 Hz); 7.86 (3H; m); 8.32(1H; br d; J=6.56 Hz); 8.46 (1H; m); 10.18 (1H; s).

Intermediate 49 9H-fluoren-9-ylmethylN-[[5-ethyl-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To a solution of 2-Fluoro-5-iodo-benzaldehyde (2.0 g, 8 mmol) indioxane: water (30 mL) were added vinyl boronic acid pinacol ester (1.6mL, 9.6 mmol) and Cs₂CO₃ (3.9 g, 12 mmol) sequentially. Then thereaction mixture was degassed with argon and Pd(PPh₃)₄(0.184 g, 0.16mmol) was added. The resulting reaction mixture was heated to 70° C. for2 h. Progress of the reaction was monitored by TLC. After completion,the reaction mixture was extracted with EtOAc (3×50 mL). Combinedorganic layer was washed with water followed by brine and dried overanhydrous sodium sulfate. Solvent was evaporated under reduced pressureto get crude compound which was further purified by flash-chromatography(hexane) to get 2-fluoro-5-vinyl-benzaldehyde (0.83 g, 69%) as colorlessoil.

To a degassed solution of 2-fluoro-5-vinyl-benzaldehyde (0.83 g, 5.5mmol) in dry DMF (4 mL) were added K₂CO₃ (1.2 g, 13.8 mmol) and methylthiosalicylate (0.91 mL, 0.66 mmol). Then the reaction mixture wasstirred for 1 h. Progress of the reaction was monitored by TLC. Aftercompletion the reaction mixture was diluted with water (30 mL) andextracted with EtOAc (3×20 mL). Combined organic layer was washed withwater followed by brine and dried over Na₂SO₄. Solvent was evaporatedunder reduced pressure to get crude compound which was purified bycombiflash (20% ethyl acetate in hexane) to afford methyl2-(2-formyl-4-vinyl-phenyl)sulfanylbenzoate (1.4 g, 85%) as yellow oil.MS found: 299.2 (M+H).

To a degassed solution of methyl2-(2-formyl-4-vinyl-phenyl)sulfanylbenzoate (1.4 g, 4.6 mmol) in ethylacetate (25 mL) was added PtO₂ (0.05 g) and the reaction mixture wasstirred under hydrogen atmosphere for 3 h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was filteredthrough celite and the filtrate was concentrated under reduced pressureto get methyl 2-(4-ethyl-2-formyl-phenyl)sulfanylbenzoate (1.4 g, 99%)as white solid. MS found: 301.0 (M+H).

To a solution of methyl 2-(4-ethyl-2-formyl-phenyl)sulfanylbenzoate (1.4g, 4.6 mmol) in THF (30 mL) was added 2-methylpropane-2-sulfinamide (1.4g, 11.66 mmol) followed by titanium ethoxide (2.4 mL, 11.66 mmol) andthe reaction mixture was heated at 55° C. for 2 h. Progress of thereaction was monitored by TLC. After completion the reaction mixture wasdiluted with water (30 mL) and filtered through celite. Organic layerwas separated off, dried over sodium sulphate and concentrated underreduced pressure to get methyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-ethyl-phenyl]sulfanylbenzoate(1.6 g, 85%) as colorless oil. MS found: 404.3 (M+H).

To an ice-cooled solution of LAH (0.471 g, 12.40 mmol) in dry THF (10mL) was added a solution of methyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-ethyl-phenyl]sulfanylbenzoate(2.5 g, 6.20 mmol) in THF (20 mL) and the resulting reaction mixture wasstirred for 0.5 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction was quenched with saturated sodium sulphatesolution (5 mL) and ethyl acetate. Then the reaction mixture wasfiltered through celite and washed with ethyl acetate (50 mL). Thefiltrate was concentrated under reduced pressure to getN-[[5-ethyl-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 93%) which was used as such in next step. MS found: 378.1 (M+H).

To an ice cold solution ofN-[[5-ethyl-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.2 g, 4.23 mmol) in acetonitrile (20 mL) was added 5% sodiumbicarbonate solution (12 mL) followed by a solution of Fmoc-Osu (1.4 g,4.29 mmol) in acetonitrile (10 mL) and the reaction mixture was stirredat ambient temperature for 4 h. Progress of the reaction was monitoredby TLC. After completion, the reaction mixture was diluted with water(50 mL) and ethyl acetate (80 mL). Organic layer was separated fromwhich volatiles were removed under reduced pressure to get crudecompound which was then purified by flash-chromatography (20% ethylacetate in hexane) to 9H-fluoren-9-ylmethylN-[[5-ethyl-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (0.670 g,35%) as white solid. LC-MS: 494.0 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 1.20 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6Hz), 4.30-4.23 (5H, m), 6.66 (1H, d, J=8.0 Hz), 7.36-7.23 (5H, m),7.48-7.38 (4H, m), 7.70 (2H, d, J=7.4 Hz), 7.83 (1H, t, J=5.9 Hz), 7.89(2H, d, J=7.5 Hz), 7.95 (1H, d, J=7.6 Hz), 10.21 (1H, s).

Intermediate 50 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-phenyl-phenyl]methyl]carbamate

A solution of 4-Fluoro-biphenyl (2 g, 11.61 mmol) and PMDTA (3 mL) inTHF (50 mL) was cooled to −78° C. and 1.6 M nBuLi (10.88 mL, 17.42 mmol)was added drop wise. The resultant reaction mixture was stirred for 40min at −60° C. The reaction mixture was cooled to −78° C. again and DMF(2.12 mL, 29.03 mmol) was added. Then the reaction mixture was stirredat −78° C. for 30 min before allowing the mixture to warm up to roomtemperature. The reaction mixture was quenched with aqueous NH₄Cl andthe whole mixture was extracted with diethyl ether (30 mL). Combinedorganic layer was washed with brine (30 mL) and concentrated underreduced pressure to afford crude compound which was purified byflash-chromatography (10% ethylacetate in hexane) to get2-fluoro-5-phenyl-benzaldehyde (1.8 g, 77%) as viscous oil.

To a solution of 2-fluoro-5-phenyl-benzaldehyde (2.5 g, 10 mmol) indioxane-water (1:1) (30 mL) was added phenyl boronic ester (1.45 g, 12mmol) and Cs₂CO₃ (4.87 g, 15 mmol) sequentially. The solution was thendegassed with argon for 30 min. To this solution was addedPd(PPh₃)₄(0.23 g, 0.2 mmol) and heated to 70° C. for 2 h. Then thereaction mixture was filtered, filtrate was concentrated and dilutedwith water (50 mL). The aq. layer was extracted with ethyl acetate (100mL×2). Combined organic layer was washed with brine (50 mL) and driedover anhydrous sodium sulphate. Organic layer was concentrated to getthe crude compound which was purified by flash-chromatography (10% ethylacetate in hexane) to afford 2-fluoro-5-phenyl-benzaldehyde (1.7 g, 85%)as viscous oil.

To a solution of 2-fluoro-5-phenyl-benzaldehyde (1.7 g, 8.5 mmol) andmethyl thiosalicylate (1.43 g, 8.5 mmol) in DMF (20 mL) was added K₂CO₃(2.35 g, 17 mmol) and the reaction mixture was heated to 60° C. for 16h. Then the reaction mixture was diluted with water and extracted withethyl acetate (100 mL×2). Combined organic layer was washed with brine(40 mL×2), dried over sodium sulphate and concentrated to afford crudecompound which was further purified by combiflash (30% ethyl acetate inhexane) to afford methyl 2-(2-formyl-4-phenyl-phenyl)sulfanylbenzoate(1.8 g, 60%) as an off-white solid. LCMS: 349.1 (M+H).

To a stirred solution of methyl2-(2-formyl-4-phenyl-phenyl)sulfanylbenzoate (1.7 g, 4.88 mmol) inanhydrous THF (50 mL) were added 2-methylpropane-2-sulfinamide (1.18 g,9.77 mmol) and titanium tetraethoxide (2.23 g, 9.77 mmol) sequentiallyand the resultant reaction mixture was heated at 60° C. for 5 h. Thenthe reaction mixture was poured onto ice-water and filtered through ashort pad of celite. Filtrate was extracted with ethyl acetate (100mL×2), washed with brine (100 mL×2), dried over anhydrous sodium sulfateand concentrated under reduced pressure to get the crude compound whichwas purified by flash-chromatography column (10-20% ethyl acetate inhexane) to afford methyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-phenyl-phenyl]sulfanylbenzoate(1.8 g, crude) as sticky mass. MS found: 452.1 (M+H).

To an ice-cooled suspension of LAH (0.279 g, 7.54 mmol) in THF (50 mL)was added a solution of methyl2-[2-[(Z)-tert-butylsulfinyliminomethyl]-4-phenyl-phenyl]sulfanylbenzoate(1.7 g, crude) in THF (50 mL) and the reaction mixture was stirred at 0°C. for 30 min. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate solution (5 mL) and diluted with ethyl acetate (20 mL). Thereaction mixture was filtered through celite and filtrate wasconcentrated to getN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-phenyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.4 g, crude) as white solid. MS found: 426.1 (M+H).

To an ice-cooled solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-phenyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g, crude) in DCM (50 mL) was added Dess-Martin periodinane (2.59 g,6.12 mmol) portion wise and the reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith DCM (50 mL) and saturated sodium bicarbonate solution (50 mL).Organic layer was separated off and the aqueous layer was extracted withDCM (50 mL×2). Combined organic layer was washed with sodiumthiosulphate solution followed by brine. Volatiles were removed underreduced pressure to getN-[[2-(2-formylphenyl)sulfanyl-5-phenyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.8 g, 40% over four steps) as viscous oil. MS found: 423.9 (M+H).

To an ice-cooled solution ofN-[[2-(2-formylphenyl)sulfanyl-5-phenyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.5 g, 3.5 mmol) in dioxane (20 mL) was added 4M HCl in dioxane and thereaction mixture was stirred at same temperature for 1 h. Volatiles wereremoved under reduced pressure to get the crude compound which wastriturated with diethyl ether to get2-[2-(aminomethyl)-4-phenyl-phenyl]sulfanylbenzaldehyde (0.9 g, 79%) aswhite solid. MS found: 320.0 (M+H).

To a stirred suspension of2-[2-(aminomethyl)-4-phenyl-phenyl]sulfanylbenzaldehyde (0.7 g, 1.88mmol) in 5% sodium bicarbonate solution (12 mL) was added a solution ofFmoc-OSu (0.443 g, 1.314 mmol) in acetonitrile (30 mL) and the reactionmixture was stirred at room temperature for 3 h. Volatiles were removedunder reduced pressure and the crude reaction mixture was diluted withwater (10 mL). Then the aq. phase was extracted with ethyl acetate (50mL×3) and washed with brine (50 mL), dried over anhydrous sodium sulfateand evaporated under reduced pressure to get the crude compound whichwas purified by flash-chromatography (10% ethyl acetate in hexane) to9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-phenyl-phenyl]methyl]carbamate (0.45 g,44%) as white solid. LC-MS: 542.2 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 4.22-4.19 (1H, m), 4.28 (2H, d, J=7.0 Hz),4.35 (2H, d, J=5.6 Hz), 6.82 (1H, d, J=7.9 Hz), 7.25 (2H, t, J=7.4 Hz),7.44-7.36 (4H, m), 7.55-7.47 (4H, m), 7.69-7.67 (5H, m), 7.76 (1H, s),7.87 (2H, d, J=7.4 Hz), 7.99-7.96 (2H, m), 10.24 (1H, s).

Intermediate 51 9H-fluoren-9-ylmethylN-[[5-tert-butyl-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To a stirred solution of 1-tert-butyl-4-flurobenzene (2.0 g, 13.15 mmol)in dry THF (20 mL) was added PMDTA (3.4 mL, 19.73 mmol) and n-BuLi (1.6M in THF, 12.3 mL, 26.31 mmol) at −78° C. and the resulting reactionmixture was stirred at the same temperature for 1 h. To the reactionmixture was added DMF (2.6 mL, 32.89 mmol) at −78° C. and stirredfurther at the same temperature for 1 h. Then the reaction mixture wasquenched by the addition of saturated NH₄Cl (20 mL) and extracted withdiethyl ether (2×25 mL). Combined organic layer was washed with water(20 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound thus obtained was purified byflash-chromatography (1% ethyl acetate in hexane) to afford5-tert-butyl-2-fluoro-benzaldehyde (2.1 g, 88%) as a pale yellow oil.

To a stirred solution of 5-tert-butyl-2-fluoro-benzaldehyde (1.3 g, 7.22mmol) in dry DMF (20 mL) were added methyl thiosalicylate (2.0 mL, 14.44mmol) and KOtBu (1.6 g, 14.44 mmol) sequentially and the resultingreaction mixture was heated to 50° C. for 16 h. Then the reactionmixture was cooled to room temperature, diluted with water (30 mL) andextracted with ethyl acetate (2×25 mL). Combined organic layer waswashed with water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound thusobtained was purified by flash-chromatography (1.8% ethyl acetate inhexane) to afford methyl2-(4-tert-butyl-2-formyl-phenyl)sulfanylbenzoate (0.7 g, 30%) as a paleyellow oil. MS found: 329.3 (M+H).

To a stirred solution of methyl2-(4-tert-butyl-2-formyl-phenyl)sulfanylbenzoate (0.7 g, 2.13 mmol) indry THF (20 mL) was added 2-methylpropane-2-sulfinamide (0.6 g, 5.33mmol) followed by titanium (IV) ethoxide (1.1 mL, 5.33 mmol) and theresulting reaction mixture was heated to 70° C. for 2 h. Then thereaction mixture was cooled to room temperature, diluted with water,filtered through celite. The filtrate was extracted with ethyl acetate(2×20 mL). Combined organic layer was washed with water (10 mL) followedby brine (10 mL) and dried over anhydrous Na₂SO₄. Organic layer wasconcentrated under reduced pressure to get the crude compound which waspurified by flash-chromatography (18% ethyl acetate in hexane) to affordmethyl2-[4-tert-butyl-2-[(E)-tert-butylsulfinyliminomethyl]phenyl]sulfanylbenzoate(0.9 g, 97%) as a pale yellow oil.

To an ice cooled solution of LAH (0.2 g, 6.26 mmol) in dry THF (20 mL)was added a solution of methyl2-[4-tert-butyl-2-[(E)-tert-butylsulfinyliminomethyl]phenyl]sulfanylbenzoate(0.9 g, 2.08 mmol) in dry THF (20 mL) and the resulting reaction mixturewas stirred at room temperature for 2 h. Then reaction mixture wasquenched with ethyl acetate (30 mL), filtered through celite andconcentrated under reduced pressure to affordN-[[5-tert-butyl-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.7 g, 82%) as a white solid.

To an ice-cooled solution ofN-[[5-tert-butyl-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.7 g, 1.72 mmol) in dry DCM (10 mL) was added Dess-Martin periodinane(0.8 g, 1.90 mmol) and the resulting reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was quenched withsaturated NaHCO₃ solution (25 mL) and extracted with DCM (2×25 mL).Combined organic layer was washed with water (15 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound thus obtained was purified by flash-chromatography (50% ethylacetate in hexane) to affordN-[[5-tert-butyl-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.55 g, 78%) as an off-white solid.

To an ice-cooled solution ofN-[[5-tert-butyl-2-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.55 g, 1.36 mmol) in dioxane (2 mL) was added 4M dioxane in HCl (2 mL)and the resulting reaction mixture was stirred at room temperature for 3h. Volatiles were reduced under reduced pressure to afford2-[2-(aminomethyl)-4-tert-butyl-phenyl]sulfanylbenzaldehyde (0.45 g,100%) as a yellow solid. The crude was used as such for the next step.

To an ice-cooled solution of2-[2-(aminomethyl)-4-tert-butyl-phenyl]sulfanylbenzaldehyde (0.45 g,1.34 mmol) in acetonitrile (10 mL) was added 5% NaHCO₃ solution (3 mL)followed by Fmoc-OSu (0.3 g, 0.94 mmol) and the resulting reactionmixture was stirred at room temperature for 5 h. Then the reactionmixture was diluted with water (10 mL) and extracted with ethyl acetate(2×20 mL). Combined organic layer was washed with water (10 mL) followedby brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound thus obtained was purified byflash-chromatography (15% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[5-tert-butyl-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate(0.45 g, 64%) as a yellow solid. LC-MS: 522.4 (M+H).

¹H-NMR: (400 MHz, CDCl₃): δ 1.34 (9H, s), 4.17 (1H, t, J=7.1 Hz), 4.34(2H, d, J=7.1 Hz), 4.46 (2H, d, J=6.2 Hz), 5.14 (1H, br), 6.76 (1H, d,J=8.2 Hz), 7.30-7.27 (3H, m), 7.42-7.32 (5H, m), 7.55-7.51 (3H, m), 7.74(2H, d, J=7.4 Hz), 7.84 (1H, d, J=7.9 Hz), 10.30 (1H, s).

Intermediate 52 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-isopropyl-phenyl]methyl]carbamate

To a solution of 5-Bromo-2-fluoro-benzaldehyde (2 g, 9.85 mmol) indioxane:water (1:1) (40 mL, 1:1) was added isoprenylboronic ester (1.98g, 11.82 mmol) and Cs₂CO₃ (8 g, 24.63 mmol) sequentially. The reactionmixture was then degassed with argon for 0.5 h and to it was addedPd(PPh₃)₄(0.22 g, 0.19 mmol). The reaction mixture was then heated at70° C. for 2 h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was filtered. The filtrate wasconcentrated and diluted with ethyl acetate (100 mL). Organic layer waswashed with water followed by brine and dried over anhydrous sodiumsulfate. Organic layer was concentrated to get the crude compound whichwas purified by flash-chromatography (20% ethyl acetate in hexane) toafford 2-fluoro-5-isopropenyl-benzaldehyde (1.2 g, 74%) as viscous oil.

To an ice-cooled solution of 2-fluoro-5-isopropenyl-benzaldehyde (1.3 g,7.92 mmol) and methyl thiosalicylate (1.59 g, 9.51 mmol) in DMF (30 mL)under argon atmosphere was added potassium carbonate (2.73 g, 19.81mmol) and the reaction mixture was heated at 60° C. for 3 h.

Then the reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (40 mL×3). The organic layer was washed with brine(40 mL×3), dried over sodium sulfate and concentrated under reducedpressure to get crude compound which was purified byflash-chromatography (30% ethyl acetate in hexane) to afford methyl2-(2-formyl-4-isopropenyl-phenyl)sulfanylbenzoate (2.2 g, 89%) as paleyellow solid. MS found: 313.1 (M+H).

To a degassed solution of methyl2-(2-formyl-4-isopropenyl-phenyl)sulfanylbenzoate (1.6 g, 5.12 mmol) inTHF (50 mL) was added Raney Ni (0.2 g) and the reaction mixture was thenstirred under hydrogen atmosphere for 16 h. Then the reaction mixturewas filtered through celite, washed with THF and concentrated underreduced pressure to get crude compound which was purified byflash-chromatography (60% ethyl acetate in hexane) to afford methyl2-[2-(hydroxymethyl)-4-isopropyl-phenyl]sulfanylbenzoate (1.4 g, 87%) asviscous oil. MS found: 317.1 (M+H).

To an ice-cooled solution of methyl2-[2-(hydroxymethyl)-4-isopropyl-phenyl]sulfanylbenzoate (1.4 g, 4.43mmol) in DCM (50 mL) was added Dess-Martin periodinane (2.25 g, 5.31mmol) portion wise and the reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith DCM (50 mL) and saturated sodium bicarbonate solution (50 mL×2).Organic layer was separated off and the aqueous layer was extracted withDCM (50 mL×2). Combined organic layer was washed with sodiumthiosulphate solution followed by brine. Volatiles were removed underreduced pressure to get the crude compound which was purified byflash-chromatography (30% ethyl acetate in hexane) to afford methyl2-(2-formyl-4-isopropyl-phenyl)sulfanylbenzoate (1.2 g, 86%) as viscousoil. MS found: 314.9 (M+H).

To a stirred solution of methyl2-(2-formyl-4-isopropyl-phenyl)sulfanylbenzoate (1.2 g, 3.82 mmol) inanhydrous THF (50 mL) were added 2-methylpropane-2-sulfinamide (1.15 g,9.55 mmol) and titanium tetraethoxide (2.17 g, 9.77 mmol) sequentially.The resultant reaction mixture was heated to 60° C. for 5 h under argonatmosphere. Then the reaction mixture was poured onto ice-water andfiltered through celite. Filtrate was extracted with ethyl acetate (100mL×2), washed with brine (100 mL×2), dried over anhydrous sodium sulfateand concentrated under reduced pressure to get the crude compound whichwas purified by flash column (10-20% ethyl acetate in hexane) to affordmethyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-isopropyl-phenyl]sulfanylbenzoate(1.45 g, 91%) as brown solid. MS found: 418.2 (M+H).

To an ice-cooled suspension of LAH (0.25 g, 6.95 mmol) in THF (30 mL)was added a solution of afford methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-4-isopropyl-phenyl]sulfanylbenzoate(1.45 g, 3.47 mmol) in THF (20 mL) and the reaction mixture was stirredfor 30 min at 0° C. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with saturated sodiumsulphate solution (5 mL) and diluted with ethyl acetate (20 mL). Thereaction mixture was filtered through celite. The filtrate wasconcentrated to affordN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-isopropyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.1 g, 81%) as white solid. MS found: 392.0 (M+H).

To an ice-cooled solution ofN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-isopropyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1 g, 2.55 mmol) in dioxane (20 mL) was added 4M HCl in dioxane and theresulting reaction mixture was stirred at room temperature for 1 h.Volatiles were removed under reduced pressure to get crude compoundwhich was triturated with diethyl ether and dried to get[2-[2-(aminomethyl)-4-isopropyl-phenyl]sulfanylphenyl]methanol (0.735 g,87%) as white solid. MS found: 287.9 (M+H).

To a stirred suspension of[2-[2-(aminomethyl)-4-isopropyl-phenyl]sulfanylphenyl]methanol (0.7 g,2.16 mmol) in 5% sodium bicarbonate solution (12 mL) was added Fmoc-OSu(0.51 g, 1.51 mmol) in acetonitrile (30 mL) and the reaction mixture wasstirred at ambient temperature for 3 h. Volatiles were concentratedunder vacuum then diluted with water (50 mL) and extracted with ethylacetate (50 mL×3) and washed with brine (50 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure to get crudecompound. Crude compound was purified by flash-chromatography (20% ethylacetate in hexane) to afford[2-(2-ethyl-4-isopropyl-phenyl)sulfanylphenyl]methanol (0.7 g, 63%) aswhite solid. MS found: 510.2 (M+H).

To an ice-cooled solution of[2-(2-ethyl-4-isopropyl-phenyl)sulfanylphenyl]methanol (0.7 g, 1.38mmol) in DCM (30 mL) was added Dess-Martin periodinane (0.75 g, 1.78mmol) portion wise and the reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was dilutedwith DCM (50 mL) and saturated sodium bicarbonate solution (50 mL×2).Organic layer was separated off and the aqueous layer was extracted withDCM (50 mL×2). Combined organic layer was washed with sodium thiosulfatesolution followed by brine. Volatiles were removed under reducedpressure to get crude compound which was purified byflash-chromatography (30% ethyl acetate in hexane) to afford9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-isopropyl-phenyl]methyl]carbamate(0.530 g, 76%) as white solid. LC-MS: 508.1 (M+H).

¹H-NMR: (400 MHz, DMSO-d6): δ 1.21 (6H, d, J=6.9 Hz), 2.92 (1H, sep,J=6.9 Hz), 4.28-4.19 (5H, m), 6.67 (1H, d, J=8.0 Hz), 7.49-7.25 (9H, m),7.70 (2H, d, J=7.4 Hz), 7.85 (1H, t, J=5.7 Hz), 7.89 (2H, d, J=7.5 Hz),7.96 (1H, d, J=7.3 Hz), 10.21 (1H, s).

Intermediate 53 9H-fluoren-9-ylmethylN-[[2-fluoro-6-(2-formylphenyl)sulfanyl-phenyl]methyl] carbamate

To a suspension methyl 2-sulfanylbenzoate (3 g, 21.11 mmol) and K₂CO₃(5.8 g, 42.22 mmol) in DMF (50 mL) was added 2,6-difluorobenzaldehyde(3.5 g, 21.11 mmol) and the reaction mixture was stirred for 2 h at roomtemperature. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×250 ml). Combined organic layer wasdried over sodium sulfate and concentrated under reduced pressure to getcrude compound which was purified by flash-chromatography (20% ethylacetate in hexane) to get compound methyl2-(3-fluoro-2-formyl-phenyl)sulfanylbenzoate (4.1 g, 67%) as brownsolid.

To a solution of methyl 2-(3-fluoro-2-formyl-phenyl)sulfanylbenzoate(2.5 g, 8.62 mmol) and 2-methylpropane-2-sulfinamide (2.60 g, 21.55mmol) in THF (100 mL) was added titanium tetraethoxide (4.9 g, 21.52mmol) and the reaction mixture was heated to 70° C. for 3 h. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(3×250 mL). Combined organic layers were dried over sodium sulphate andconcentrated under reduced pressure to get crude methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-fluoro-phenyl]sulfanylbenzoate(3.2 g, 94%) which was used as such in next step without purification.LC-MS: 393.8 (M+H).

To an ice cooled suspension of LAH (0.9 g, 25.95 mmol) was added asolution of methyl2-[2-[(E)-tert-butylsulfinyliminomethyl]-3-fluoro-phenyl]sulfanylbenzoate(3.4 g, 8.65 mmol) in THF (50 mL) and the reaction mixture was stirredfor 1 h at same temperature. Progress of the reaction was monitored byTLC. After completion, the reaction mixture was diluted with aq. sodiumsulfate solution (50 mL) and extracted with ethyl acetate (3×100 mL).Combined organic layers were dried over sodium sulfate and concentratedunder reduced pressure to get crude compound which was washed withhexane and pentane to getN-[[2-fluoro-6-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.8 g, 88%) as brown solid. LC-MS: 367.7 (M+H).

To a solution ofN-[[2-fluoro-6-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.8 g, 7.62 mmol) in DCM (50 mL) was added Dess-Martin periodinane(8.07 g, 19.04 mmol) and the reaction mixture was stirred at RT for 2 h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with sodium bicarbonate solution (100 mL)and extracted with DCM (3×100 mL). Combined organic layers were driedover sodium sulphate and concentrated under reduced pressure to getcrude compound which was purified by silica-gel column chromatography toget solidN-[[2-fluoro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g, 72%) as white solid. LC-MS: 365.7 (M+H).

To an ice cooled solution ofN-[[2-fluoro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(1.8 g, 2.88 mmol) in dioxane (40 mL) was added 4M HCl in dioxane (20mL) and the reaction mixture was stirred for 2 h at room temperature.Progress of the reaction was monitored by TLC. Volatiles were removedunder reduced pressure and the crude compound was triturated withdiethyl ether to get2-[2-(aminomethyl)-3-fluoro-phenyl]sulfanylbenzaldehyde (2 g, crude) aswhite solid. LC-MS: 361.7 (M+H).

To a suspension of2-[2-(aminomethyl)-3-fluoro-phenyl]sulfanylbenzaldehyde (2 g, 4.96 mmol)in 5% aqueous NaHCO₃ (15 mL) was added a solution of Fmoc-OSu (1.1 g,3.47 mmol) in acetonitrile (50 mL) and the reaction mixture was stirredat ambient temperature for 3 h. Then the reaction mixture was dilutedwith ethyl acetate and washed with water followed by brine. Organiclayer was dried over sodium sulfate and evaporated under reducedpressure to get crude compound which was purified byflash-chromatography to get 9H-fluoren-9-ylmethylN-[[2-fluoro-6-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate (0.550g, 16% over two steps) as off white solid. LC-MS: 483.9 (M+H).

Intermediate 54 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To an ice-cooled solution of sodium chlorite (6.81 g, 75.68 mmol) inwater (30 mL) was added a solution of 3-Chloro-2-fluoro-benzaldehyde (3g, 18.92 mmol) in acetone (75 mL) and the reaction mixture was stirredfor 5 min. To the resulting reaction mixture was added sulphamic acid(5.50 g, 56.761 mmol) in one lot at 0° C. and stirring continued for 30min. Progress of the reaction was monitored by TLC. After completion,the reaction mixture was diluted with water (5 mL) and filtered.Filtrate was extracted with ethyl acetate (3×50 mL), combined organiclayer was dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get 3-chloro-2-fluoro-benzoicacid (3.2 g, 97%) as white solid. LC-MS: 172.9 (M−H).

To a solution of 3-chloro-2-fluoro-benzoic acid (0.55 g, 3.151 mmol) inmethanol (20 mL) was added conc. sulfuric acid (1 mL) and the reactionmixture was heated to 80° C. for 16 h. Volatiles were concentrated underreduced pressure and the crude reaction mixture was diluted with ethylacetate. Then the reaction mixture was washed with saturated sodiumbicarbonate solution followed by brine. Organic layers were dried overanhydrous sodium sulphate, filtered and concentrated to get methyl3-chloro-2-fluoro-benzoate (0.5 g, 84%) as colorless liquid.

To a stirred solution of methyl 3-chloro-2-fluoro-benzoate (0.05 g,0.265 mmol) in DMF (2 mL) was added Na₂S (0.05 g) and the reactionmixture was heated to 70° C. for 5 h. Then the reaction mixture wasacidified with 10% HCl and extracted with EtOAc (3×25 mL). Combinedorganic layers were washed with water followed by brine, dried overanhydrous sodium sulphate and concentrated to get methyl3-chloro-2-sulfanyl-benzoate (0.035 g, crude) as yellow solid. LC-MS:201.1 (M−H).

To a stirred solution of methyl 3-chloro-2-sulfanyl-benzoate (0.05 g,0.247 mmol) in DMF (2 mL) were added K₂CO₃ (136 mg, 0.987 mmol) and2-fluoro-pyridine-3-carbaldehyde (61 mg, 0.493 mmol) sequentially andthe reaction mixture was heated to 70° C. for 16 h. Then the reactionmixture was diluted with EtOAc and washed with brine. The organic layerwas dried over anhydrous sodium sulphate, filtered and concentrated toget the crude compound which was purified by column chromatography (25%ethyl acetate in hexane) to get methyl3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]benzoate (0.015 g, 12% over twosteps) as white solid. LC-MS: 308.0 (M+H).

A mixture of methyl 3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]benzoate(1.3 g, 4.23 mmol), ethylene glycol (0.789 g, 12.70 mmol), p-TSA (0.081g, 0.423 mmol) in toluene (30.0 mL) was heated to 140° C. for 2 h.Progress of the reaction was monitored by TLC. Then the reaction mixturewas diluted with water (100 mL) and the aqueous phase was extracted withethyl acetate (50 mL×2). Combined organic layers were dried overanhydrous sodium sulfate and solvent distilled-off under reducedpressure to get crude methyl3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]benzoate (1.4 g,94%) as colorless oil which was used as such in next step. LC-MS: 351.9(M+H).

To an ice-cooled solution of methyl3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]benzoate (1.4 g,crude) in THF (25 mL) was added LAH powder in batches (0.302 g, 7.96mmol) and the reaction mixture was stirred for 30 min at RT. Then thereaction mixture was quenched with ethyl acetate and saturated sodiumsulphate solution. Then the reaction mixture was filtered through celiteand filtrate was extracted with ethyl acetate. The organic layer waswashed with brine solution and dried over sodium sulphate, filtered andconcentrated to get the crude compound which was further purified bycolumn chromatography (50% ethyl acetate in hexane) to get[3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methanol(1.2 g, 93%) as white solid. LC-MS: 324.1 (M+H).

A solution of[3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methanol(1 g, crude), triphenyl phosphine (2.5 g, 0.040 mmol), sodium azide (2g, 0.007 mmol) in carbon tetrachloride (0.1 mL) and DMF (5.0 ml) washeated to 70° C. for 3 h. Progress of the reaction was monitored by TLC.The reaction mixture was diluted with water (20 mL) and the aqueousphase was extracted with ethyl acetate (30 mL×2). Combined organiclayers were dried over anhydrous sodium sulfate and solventdistilled-off under reduced pressure to get the crude compound which waspurified by column chromatography (30% ethyl acetate in hexane) to get2-[2-(azidomethyl)-6-chloro-phenyl]sulfanyl-3-(1,3-dioxolan-2-yl)pyridine(0.12 g, 11%) as viscous oil. LC-MS: 348.9 (M+H).

To a stirred solution of2-[2-(azidomethyl)-6-chloro-phenyl]sulfanyl-3-(1,3-dioxolan-2-yl)pyridine(0.45 g, 1.29 mmol) in ethanol (20 mL) was added Pd—C (0.138 g, 7.96mmol) and the reaction mixture was agitated under hydrogen pressure for16 h. Then the reaction mixture was filtered through celite and thefiltrate was concentrated in vacuo to get[3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methanamine(0.350 g, 83%) as viscous oil which was used as such in next stepwithout further purification. LC-MS: 322.9 (M+H).

To a solution of[3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methanamine(0.35 g, crude) in 5% sodium bicarbonate (0.5 mL) was added Fmoc-OSu(0.31 g, 0.93 mmol) in acetonitrile (10 mL) and the reaction mixture wasstirred at room temperature for 3 h. Progression of the reaction wasmonitored by TLC. After completion, volatiles were removed under reducedpressure and the crude reaction mixture was diluted with water (10 mL).The aqueous phase was extracted with ethyl acetate (10 mL×3). Combinedorganic layers were washed with brine (10 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure to get crudecompound. The crude compound was purified by combiflash (30% ethylacetate in hexane) to afford desired compound which was further washedwith diethyl ether (5 mL) followed by pentane (5 mL) and dried to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(0.300 g, 59%) as an off-white solid. LC-MS: 544.9 (M+H).

To a solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(0.3 g, 0.642 mmol) in of acetone (10 mL) was added conc. HCl (2 mL) andthe reaction mixture was stirred for 4 h at room temperature. Aftercompletion, volatiles were removed under reduced pressure and the crudereaction mixture was quenched with saturated sodium bicarbonatesolution. Then the resulting reaction mixture was extracted with ethylacetate (3×25 mL). Combined organic layers were washed with brinesolution, dried over anhydrous sodium sulphate, filtered andconcentrated to get crude compound which was purified byflash-chromatography (50% ethyl acetate in hexane) to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(0.115 g, 36%) as an off-white solid. LC-MS: 500.9 (M+H).

¹H-NMR (400 MHz, CDCl-3): δ 4.13-4.16 (1H; m); 4.39 (2H; d; J=6.76 Hz);4.57 (2H; d; J=6.76 Hz); 7.18-7.20 (1H; m); 7.26-7.29 (1H; m): 7.35-7.39(3H; m); 7.37-7.50 (4H; m); 7.74 (2H; d; J=7.56 Hz); 7.74-7.79 (1H; m);8.29-8.30 (1H; m); 10.45 (1H: s).

Intermediate 553-{(S)-2-Carboxy-2-[ethyl-(9H-fluoren-9-ylmethoxycarbonyl)-amino]-ethyl}-indole-1-carboxylicacid tert-butyl ester

A solution of (2S)-2-amino-3-(1-tert-butoxycarbonylindol-3-yl)propanoicacid (2 g, 6.57 mmol), o-nitrobenzenesulfonylchloride (1.64 g, 7.42mmol) in saturated sodium carbonate solution and dioxane (132 mL, 1:1)was stirred for 18 h. Then the pH of the solution was adjusted to 7.0with 0.5 M HCl. Solvent was removed under reduced pressure and the crudereaction mixture was extracted with ether (3×50 mL). Combined organiclayer was washed with water, dried over sodium sulfate and concentratedto afford(2S)-3-(1-tert-butoxycarbonylindol-3-yl)-2-[(2-nitrophenyl)sulfonylamino]propanoicacid (2.4 g, 75%) as a yellow solid. To a solution of(2S)-3-(1-tert-butoxycarbonylindol-3-yl)-2-[(2-nitrophenyl)sulfonylamino]propanoicacid (1.6 g, 3.26 mmol) in dry DMF (25 mL) were added potassiumcarbonate (1.5 g, 11.44 mmol) and ethyl iodide (1.5, 9.8 mmol)sequentially and the reaction mixture was stirred for 8 h. Then thereaction mixture was poured onto water (25 mL) and the aqueous layer wasextracted with ether (3×30 mL). Combined organic layers were washed withwater, dried over sodium sulfate and concentrated under reduced pressureto get the crude compound which was purified by flash-chromatography(20% ethyl acetate in hexane) to afford tert-butyl3-[(2S)-3-ethoxy-2-[ethyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-1-carboxylate(0.3 g, 17%) as viscous oil. LC-MS: 544.1 (M−H).

To a solution of tert-butyl3-[(2S)-3-ethoxy-2-[ethyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-1-carboxylate(3.4 g, 6.2 mmol) in dry DMF (50 mL) were added K₂CO₃ (2.5 g, 18.72mmol) and thiophenol (0.825 g, 7.4 mmol) sequentially and the reactionmixture was stirred for 2 h at RT. After completion, the reactionmixture was quenched with water (50 mL) and extracted with ethyl acetate(100 mL×3). Organic layer was separated off, washed with water (50 mL×2)and dried over Na₂SO₄. The organic layer was evaporated under reducedpressure and the crude compound thus obtained was purifiedby—chromatography (20% ethyl acetate in hexane) to afford tert-butyl3-[(2S)-3-ethoxy-2-(ethylamino)-3-oxo-propyl]indole-1-carboxylate (1.5g, 67%) as viscous mass. LC-MS: 361.0 (M+H).

To a solution of tert-butyl3-[(2S)-3-ethoxy-2-(ethylamino)-3-oxo-propyl]indole-1-carboxylate (1.5g, 4.17 mmol) in THF—water (40 mL, 3:1) was added LiOH (0.21 g 5.0 mmol)and the reaction mixture was stirred for 24 h at room temperature. Aftercompletion, the reaction mixture was neutralized with 0.5 N HCl andevaporated under reduced pressure. The crude compound obtained waswashed with water (50 mL) and dried well to afford(2S)-3-(1-tert-butoxycarbonylindol-3-yl)-2-(ethylamino)propanoic acid(1.3 g, 96%) as white solid. LC-MS: 332.9 (M+H).

To a solution of(2S)-3-(1-tert-butoxycarbonylindol-3-yl)-2-(ethylamino)propanoic acid(1.4 g, 4.2 mmol) in THF: water (40 mL, 1:1) was added 5% NaHCO₃followed by Fmoc-OSU (1.4 g, 4.2 mmol) and the reaction mixture wasstirred for 5 h at room temperature. Then the reaction mixture wasdiluted with water and extracted with ethyl acetate (50 mL×3). Organiclayer was separated off, dried over sodium sulfate and concentratedunder reduced pressure to get the crude compound which was purified byflash-chromatography (50% ethyl acetate in hexane) to afford desiredcompound. The compound thus obtained was dried by adding toluene to itand distilling the toluene (10 mL×5). The resulting solid was washedwith diethyl ether-n-pentane (20 mL, 1:4) and dried to get(2S)-3-(1-tert-butoxycarbonylindol-3-yl)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoicacid (0.48 g, 21%) as an off-white solid. LC-MS: 554.9 (M+H).

Intermediate 56[5-Bromo-2-(3-formyl-pyridin-2-ylsulfanyl)-3-methyl-benzyl]-carbamicacid 9H-fluoren-9-ylmethyl ester

To a stirred solution of 2-Mercapto-nicotinic acid (3.94 g, 25.3 mmol)in DMF (60 mL) was added NaH (1.844 g, 46.076 mmol) at 0° C. and theresulting reaction mixture was stirred at 25° C. for 1 h. Then5-Bromo-2-fluoro-3-methyl-benzaldehyde (5 g, 23 mmol) was added to thereaction mass and it was heated to 80° C. for 32 h. After completion ofstarting material, the reaction mixture was cooled to room temperature,were added K₂CO₃ (9.6 g, 69.1 mmol) and methyl iodide (4.4 ml, 69.1mol), stirred at 25° C. for 16 h. The reaction mixture was diluted withwater, extracted with EtOAc. The separated organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to get crude material, which was purified by normalsilica-gel (100-200 mesh) column chromatography eluting with 12% EtOAcin hexane to get 2-(4-Bromo-2-formyl-6-methyl-phenylsulfanyl)-nicotinicacid methyl ester (2.5 g, 29%) as yellow solid. LC-MS: 366.0 [M+H]⁺.

To a stirred solution of2-(4-Bromo-2-formyl-6-methyl-phenylsulfanyl)-nicotinic acid methyl ester(2.55 g, 6.9 mmol) in THF (15 mL), 2-methylpropane-2-sulfinamide (770mg, 6.9 mmol) and Ti(OEt)₄ (7.3 ml, 34.8 mmol) were added at roomtemperature and the reaction mixture was heated to 70° C. for 16 h. Thereaction mixture was quenched with brine, filtered through celite bedand washed with ethyl acetate. The organic layer was separated, dried onanhydrous Na₂SO₄, concentrated to get crude material, which was purifiedby column chromatography eluting with 10% EtOAc in hexane to get thedesired compound2-(4-Bromo-2-methyl-6-{[(Z)-2-methyl-propane-2-sulfinylimino]-methyl}-phenylsulfanyl)-nicotinicacid ethyl ester (2.75 g, 82%) as off-white solid. LC-MS: 485.0 [M+H]⁺.

To a stirred and degassed solution of2-(4-Bromo-2-methyl-6-{[(Z)-2-methyl-propane-2-sulfinylimino]-methyl}-phenylsulfanyl)-nicotinicacid ethyl ester (3.11 g, 6.6 mmol) in THF (15 mL), was added LAH (1M inTHF, 13 ml, 13.3 mmol) at 0° C. and reaction mass was stirred at 25° C.for 1 h. The reaction mixture was quenched with saturated Na₂SO₄solution and extracted with EtOAc. The separated organic layer waswashed with water, brine and dried (Na₂SO₄) and concentrated to get2-Methyl-propane-2-sulfinic acid5-bromo-2-(3-hydroxymethyl-pyridin-2-ylsulfanyl)-3-methyl-benzylamide(2.3 g, 78%) as off white solid. LC-MS: 445.0[M+H]⁺.

To a stirred solution of 2-Methyl-propane-2-sulfinic acid5-bromo-2-(3-hydroxymethyl-pyridin-2-ylsulfanyl)-3-methyl-benzylamide (3g, 6.8 mmol) in Methanol (20 mL) was added 4M HCl in 1,4-dioxane (20 mL)at 0° C., and stirred for 2 h at the same temperature. After completionof starting material, reaction mixture was concentrated to get[2-(2-Aminomethyl-4-bromo-6-methyl-phenylsulfanyl)-pyridin-3-yl]-methanolHCl salt (2.6 g, crude) as off white solid. This crude was used for thenext step with out further purification.

To a stirred solution of[2-(2-Aminomethyl-4-bromo-6-methyl-phenylsulfanyl)-pyridin-3-yl]-methanol(2.6 g, 6.9 mmol) in 5% NaHCO₃ solution (15 mL) Fmoc-OSU (2.4 g, 6.9mmol) in CH₃CN (15 ml) was added at 25° C., and stirring was continuedat the same temperature for 3 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine, dried over sodium sulfate and evaporated underreduced pressure to get crude material which was purified by washingwith n-pentane to get the desired compound[5-Bromo-2-(3-hydroxymethyl-pyridin-2-ylsulfanyl)-3-methyl-benzyl]-carbamicacid 9H-fluoren-9-ylmethyl ester (3.6 g, 92%) as off white solid. LC-MS:561.1[M+H]⁺.

To a stirred solution of[5-Bromo-2-(3-hydroxymethyl-pyridin-2-ylsulfanyl)-3-methyl-benzyl]-carbamicacid 9H-fluoren-9-ylmethyl ester (6.4 g, 11.4 mmol) in DCM:THF (1:1, 60ml), MnO₂ (20 g, 228 mmol) was added at room temperature, and stirringwas continued at the same temperature for 2 h. After consuming ofstarting material as monitored by silica gel TLC, the reaction mixturewas filtered through celite pad, the filtrate was evaporated underreduced pressure. The crude material obtained was washed with n-Pentaneand n-Hexane to get[5-Bromo-2-(3-formyl-pyridin-2-ylsulfanyl)-3-methyl-benzyl]-carbamicacid 9H-fluoren-9-ylmethyl ester (5.5 g, 86%). LC-MS: 560.1 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 2.36 (3H, s), 4.22-4.26 (5H, m), 7.33-7.39(7H, m), 7.54 (1H, brs), 7.63 (2H, d, J=7.2 Hz), 7.81 (1H, m), 7.90 (2H,d, J=7.3 Hz), 8.32 (1H, m), 8.41 (1H, m), 10.20 (1H, s).

Intermediate 57 9H-fluoren-9-ylmethylN-({2-[(3-formylpyridin-2-yl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl) carbamate

To a stirred solution of 2-mercapto nicotinic acid (3.2 g, 20.3 mmol) inDMF (50 mL) was added NaH (60%, 1.47 g, 36.9 mmol) and reaction mass wasstirred at 25° C. for 30 min. Then5-bromo-2-fluoro-3-trifluoromethyl-benzaldehyde (5.0 gm, 18.5 mmol) wasadded and reaction mixture was stirred at 80° C. for 1 h. Then K₂CO₃(7.6 g, 55.3 mmol) was added followed by addition of MeI (3.4 mL, 55.3mmol) and reaction mass was stirred at 25° C. for 2 h. Reaction mass wasquenched with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine, dried over anhydrous sodium sulfateand evaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 0-30% ethyl acetate in hexane toget methyl2-{[4-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanyl}pyridine-3-carboxylate(5 g, 64%) as a yellow solid.

To a stirred solution of methyl2-{[4-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanyl}pyridine-3-carboxylate(4.5 g, 10.7 mmol) in THF (100 mL) were added2-methylpropane-2-sulfinamide (2.6 g, 21.4 mmol), Ti(OEt)₄ (6.7 mL, 32.1mmol) and reaction mass was heated to 70° C. for 1 h. The reaction masswas quenched with saturated sodium chloride solution, solid obtained wasfiltered through celite pad, washed with ethyl acetate. The separatedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford methyl2-({4-bromo-2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-6-(trifluoromethyl)phenyl}sulfanyl)pyridine-3-carboxylate (5.5 g, crude) which was directly used for nextstep without further purification. LC-MS: 523.0 [M+H]⁺.

To a stirred solution of methyl2-({4-bromo-2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-6-(trifluoromethyl)phenyl}sulfanyl)pyridine-3-carboxylate(5.5 g, 10.5 mmol) in THF (100 mL) was added LAH (2M in THF, 10.5 mL, 21mmol) at 0° C. and reaction mass was stirred at 0° C. for 1 h. Reactionmixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to getN-[(5-bromo-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3-(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(5.0 g, crude) which was directly used for next step without furtherpurification. LC-MS: 496.7 [M+H]⁺.

To a stirred solution ofN-[(5-bromo-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3-(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(3.6 g, 7.2 mmol) in DCM (50 mL) were added imidazole (1.5 g, 21.7 mmol)and TBDMSCl (1.6 gm, 10.9 mmol) at 0° C. and stirred at 25° C. for 2 h.Reaction mass was quenched with aq NaHCO₃ solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over sodium sulfate and evaporated under reducedpressure. The crude thus obtained was purified by combiflash columnchromatography using 20% ethyl acetate in hexane to getN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(3.1 g, 70%, 3 steps) as off white solid. LC-MS: 611.1 [M+H]⁺.

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(250 mg, 0.4 mmol) in toluene (8 mL) were added phenyl boronic acid(140.5 mg, 0.7 mmol), Na₂CO₃ (129.9 mg, 1.2 mmol), water (2.0 ml) anddegassed for 10 min in argon atmosphere. Then to it was addedPd(PPh₃)₄(47.23 mg, 0.04 mmol) and again degassed for 5 min. Thereaction mass was heated to 100° C. for 12 h. Reaction mixture was thencooled to 25° C., filtered through celite pad and washed with EtOAc. Theseparated organic layer was washed with brine, dried over sodium sulfateand concentrated under vacuum to get the crude material which waspurified by combiflash column chromatography using 0-25% ethyl acetatein hexane to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(200 mg, 80%) as colourless sticky liquid. LC-MS: 609.0 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.2 g, 3.6 mmol) in MeOH (20 mL), was added 4M HCl in dioxane (10 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-4-phenyl-6-(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.2 g, crude) which was directly used for next step. LC-MS:390.7 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-4-phenyl-6-(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.2 g, 3.1 mmol) in 5% NaHCO₃ (30 mL) was added Fmoc-OSU (1.13g, 3.35 mmol) in dioxan (30 mL) at 25° C. and reaction mass was stirredat the same temperature for 3 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine, dried over sodium sulfate and evaporated underreduced pressure. The crude material obtained was purified by columnchromatography (10%-30% ethylacetate-hexane) to get9H-fluoren-9-ylmethylN-[(2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-phenyl-3-(trifluoromethyl)phenyl)methyl]carbamate(1.5 g, 79%, 2 steps) as white solid.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-phenyl-3-(trifluoromethyl)phenyl)methyl]carbamate(1.5 g, 2.45 mmol) in DCM:THF (1:1, 50 mL) was added MnO₂ (3.15 g, 36.7mmol) and reaction mass was stirred at 25° C. for 4 h. The reaction masswas filtered through celite pad and filtrate was evaporated underreduced pressure. The crude material obtained was purified by combiflashchromatography (10%-30% ethylacetate-hexane) to get9H-fluoren-9-ylmethylN-({2-[(3-formylpyridin-2-yl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl)carbamate(1.0 g, 66%) as white solid with 95.56% purity. LC-MS: 611.2 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 3.98-4.08 (1H, m), 4.21 (1H, d, J=5.9 Hz),4.27 (3H, d, J=6.6 Hz), 7.24 (2H, t, J=6.3 Hz), 7.36-7.40 (3H, m), 7.51(4H, dq, J=13.3, 6.8 Hz), 7.67 (2H, d, J=7.1 Hz), 7.78 (3H, d, J=7.4Hz), 7.87 (2H, d, J=7.5 Hz), 7.89-7.97 (1H, m), 8.00 (2H, d, J=17.9 Hz),8.37-8.47 (2H, m), 10.20 (1H, s).

Intermediate 58 9H-fluoren-9-ylmethylN-({5-bromo-2-[(3-formylpyridin-2-yl)sulfanyl]-3-(trifluoromethyl)phenyl}methyl) carbamate

To a stirred solution of 2-mercapto nicotinic acid (3.2 g, 20.3 mmol) inDMF (50 mL) was added NaH (60%, 1.47 g, 36.9 mmol) and reaction mass wasstirred at 25° C. for 30 min. Then5-bromo-2-fluoro-3-trifluoromethyl-benzaldehyde (5.0 gm, 18.5 mmol) wasadded and reaction mixture was stirred at 80° C. for 1 h. Then K₂CO₃(7.6 g, 55.3 mmol) was added followed by addition of MeI (3.4 mL, 55.3mmol) and reaction mass was stirred at 25° C. for 2 h. Reaction mass wasquenched with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine, dried over anhydrous sodium sulfateand evaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 0-30% ethyl acetate in hexane toget methyl2-{[4-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanyl}pyridine-3-carboxylate(5 g, 64%) as a yellow solid.

To a stirred solution of methyl2-{[4-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanyl}pyridine-3-carboxylate(4.5 g, 10.7 mmol) in THF (100 mL) were added2-methylpropane-2-sulfinamide (2.6 g, 21.4 mmol), Ti(OEt)₄ (6.7 mL, 32.1mmol) and reaction mass was heated to 70° C. for 1 h. The reaction masswas quenched with saturated sodium chloride solution, solid obtained wasfiltered through celite pad, washed with ethyl acetate. The separatedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford methyl2-({4-bromo-2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-6-(trifluoromethyl)phenyl}sulfanyl)pyridine-3-carboxylate (5.5 g, crude) which was directly used for nextstep without further purification. LC-MS: 523.0 [M+H]⁺.

To a stirred solution of methyl2-({4-bromo-2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-6-(trifluoromethyl)phenyl}sulfanyl)pyridine-3-carboxylate(5.5 g, 10.5 mmol) in THF (100 mL) was added LAH (2M in THF, 10.5 mL,21.0 mmol) at 0° C. and reaction mass was stirred at 0° C. for 1 h.Reaction mixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to getN-[(5-bromo-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3-(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(5.0 g, crude) which was directly used for next step without furtherpurification. LC-MS: 496.7 [M+H]⁺.

To a stirred solution ofN-[(5-bromo-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3-(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(1.5 g, 3.0 mmol) in MeOH (50 mL), was added 4M HCl in dioxane (8 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-4-bromo-6-(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1 g) which was directly used for next step. LC-MS: 392.7[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-4-bromo-6-(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.2 g, 2.8 mmol) in 5% NaHCO₃ (120 mL) was added Fmoc OSU(1.04 g, 3.1 mmol) in dioxan (50 mL) at 25° C. and reaction mass wasstirred at the same temperature for 3 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine, dried over sodium sulfate and evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn 10%-30% ethyl acetate-hexane to get 9H-fluoren-9-ylmethylN-[(5-bromo-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3-(trifluoromethyl)phenyl)methyl]carbamate(1.2 g, 68%, 2 steps) as off white solid. LC-MS: 617.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(5-bromo-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3-(trifluoromethyl)phenyl)methyl]carbamate(1.5 g, 2.4 mmol) in DCM:THF (1:1, 50 mL) was added MnO₂ (3.14 g, 36.6mmol) and reaction mass was stirred at 25° C. for 4 h. The reaction masswas filtered through celite pad; filtrate was evaporated under reducedpressure. The crude material obtained was purified by combiflashchromatography eluting with 10%-30% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({5-bromo-2-[(3-formylpyridin-2-yl)sulfanyl]-3-(trifluoromethyl)phenyl}methyl)carbamate(700 mg, 46%) as white solid with 95.13% purity. LC-MS: 615.1 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.21-4.30 (5H, m), 7.31-7.34 (2H, m),7.40-7.41 (3H, m), 7.68 (3H, m), 7.69 (2H, d, J=7.0 Hz), 7.81 (1H, m),7.80-7.90 (3H, m), 8.01 (1H, m), 8.37-8.39 (2H, m), 10.16 (1H, s).

Intermediate 59 9H-fluoren-9-ylmethylN-({5-bromo-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate

To a stirred solution of 2-mercapto nicotinic acid (10.7 g, 69.5 mmol)in DMF (150 mL) was added NaH (60%, 5.1 g, 126.3 mmol) and reaction masswas stirred at 25° C. for 30 min. Then5-bromo-3-chloro-2-fluoro-benzaldehyde (15 g, 63.1 mmol) was added andreaction mixture was stirred at 70° C. for 4 h. Then K₂CO₃ (26.1 g,189.5 mmol) was added followed by addition of MeI (11.8 mL, 189.5 mmol)and reaction mass was stirred at 25° C. for 16 h. Reaction mass wasquenched with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine, dried over anhydrous sodium sulfateand evaporated under reduced pressure. The crude thus obtained waspurified by normal silica column using 0-8% ethyl acetate in hexane toget methyl2-[(4-bromo-2-chloro-6-formylphenyl)sulfanyl]pyridine-3-carboxylate (12g, 49%) as a yellow solid.

To a stirred solution of methyl2-[(4-bromo-2-chloro-6-formylphenyl)sulfanyl]pyridine-3-carboxylate (15g, 38.9 mmol) in THF (80 mL) were added 2-methylpropane-2-sulfinamide(4.71 g, 38.9 mmol), Ti(OEt)₄ (40.7 mL, 194.3 mmol) and reaction masswas heated to 70° C. for 2 h. The reaction mass was quenched withsaturated sodium chloride solution, solid obtained was filtered throughcelite pad, washed with ethyl acetate. The separated organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford ethyl2-({4-bromo-2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate(17 g, crude) which was directly used for next step without furtherpurification. LC-MS: 502.7 [M+H]⁺.

To a stirred solution of ethyl2-({4-bromo-2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate(17 g, 33.8 mmol) in THF (80 mL) was added LAH (2M in THF, 25.3 mL, 50.7mmol) at 0° C. and reaction mass was stirred at 0° C. for 1 h. Reactionmixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to getN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(16 g) as off-white solid. LC-MS: 464.8 [M+H]⁺.

To a stirred solution ofN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(12 g, 12.9 mmol) in MeOH (30 mL), was added 4M HCl in dioxane (30 mL)at 0° C. and reaction mixture was stirred at 25° C. for 1 h. Reactionmass was evaporated under reduced pressure to get(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methanaminiumHCl salt (4.5 g) which was directly used for next step.

To a stirred suspension of(2-{[2-(aminomethyl)-3-bromo-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (2.5 g, 6.5 mmol) in 5% NaHCO₃ (100 mL) was added Fmoc OSU (2.4g, 7.1 mmol) in dioxan (50 mL) at 25° C. and reaction mass was stirredat the same temperature for 16 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 0-50% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]carbamate(1.9 g, 50%, 4 steps) as off white solid. LC-MS: 583.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]carbamate(2.3 g, 3.9 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (3.4 g, 39.6mmol) and reaction mass was stirred at 25° C. for 16 h. The reactionmass was filtered through celite pad; filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 0-30% ethyl acetatel in hexane to get 9H-fluoren-9-ylmethylN-({5-bromo-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate (1.9 g, 82%) as off white solid with 97.5% purity. LC-MS:580.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.26 (2H, d, J=5.8 Hz), 4.29 (2H, d, J=6.8Hz), 7.33 (2H, t, J=7.3 Hz), 7.41 (3H, q, J=5.8, 4.4 Hz), 7.51 (1H, s),7.68 (2H, d, J=7.4 Hz), 7.86-7.91 (4H, m), 8.38 (1H, d, J=7.4 Hz), 8.43(1H, d, J=3.3 Hz), 10.18 (1H, s).

Intermediate 60 9H-fluoren-9-ylmethylN-({6-bromo-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl] phenyl}methyl)carbamate

To a stirred solution of 2-mercapto nicotinic acid (2.4 g, 15.5 mmol) inDMF (25 mL) was added NaH (60%, 1.23 g, 30.95 mmol) and reaction masswas stirred at 25° C. for 30 min. Then6-bromo-3-chloro-2-fluoro-benzaldehyde (4.05 g, 17.05 mmol) was addedand reaction mixture was stirred at 90° C. for 16 h. Then K₂CO₃ (6.4 g,46.4 mmol) was added followed by addition of MeI (2.9 mL, 46.4 mmol) andreaction mass was stirred at 25° C. for 5 h. Reaction mass was quenchedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 0-30% ethyl acetate in hexane toget methyl2-[(3-bromo-6-chloro-2-formylphenyl)sulfanyl]pyridine-3-carboxylate (4g, 67%) as a yellow solid. LC-MS: 387.9 [M+H]⁺.

To a stirred solution of methyl2-[(3-bromo-6-chloro-2-formylphenyl)sulfanyl]pyridine-3-carboxylate (5.0g, 12.9 mmol) in THF (50 mL) were added 2-methylpropane-2-sulfinamide(1.57 g, 12.9 mmol), Ti(OEt)₄ (8.147 ml, 38.9 mmol) and reaction masswas heated to 70° C. for 45 min. The reaction mass was quenched withsaturated sodium chloride solution, solid obtained was filtered throughcelite pad, washed with ethyl acetate. The separated organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford ethyl2-({3-bromo-6-chloro-2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate(6 g, crude) which was directly used for next step without furtherpurification. LC-MS: 504.6 [M+H]⁺.

To a stirred solution of ethyl2-({3-bromo-6-chloro-2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate(6.0 g, 11.9 mmol) in THF (50 mL) was added LAH (2M in THF, 8.9 mL, 17.9mmol) at 0° C. and reaction mass was stirred at 0° C. for 1 h. Reactionmixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 50-90% ethyl acetate in hexane to getN-[(6-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(4.0 g) as off-white solid. LC-MS: 464.9 [M+H]⁺.

To a stirred solution ofN-[(6-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(4.0 g, 8.6 mmol) in MeOH (40 mL), was added 4M HCl in dioxane (20 mL)at 0° C. and reaction mixture was stirred at 25° C. for 20 min. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-3-bromo-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (4 g) which was directly used for next step.

To a stirred suspension of(2-{[2-(aminomethyl)-3-bromo-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (4.0 g, 11.1 mmol) in 5% NaHCO₃ (25 mL) was added Fmoc-OSU (3.7g, 11.1 mmol) in CH₃CN (25 mL) at 25° C. and reaction mass was stirredat the same temperature for 3 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(6-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]carbamate(4.5 g) which was directly used for next step. LC-MS: 582.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(6-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]carbamate(2.0 g, 3.4 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (3 g, 34.4mmol) and reaction mass was stirred at 25° C. for 1 h. The reaction masswas filtered through celite pad, the filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 0-10% methanol in DCM to get 9H-fluoren-9-ylmethylN-({6-bromo-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate(1.3 g) as off white solid with 90.7% LCMS purity. LC-MS: 581.1 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.14-4.25 (3H, m), 4.46 (2H, d, J=3.9 Hz),7.31 (2H, t, J=7.5 Hz), 7.34-7.45 (3H, m), 7.48-7.54 (1H, m), 7.56 (1H,d, J=8.5 Hz), 7.67 (2H, d, J=7.4 Hz), 7.81 (1H, d, J=8.6 Hz), 7.88 (2H,d, J=7.6 Hz), 8.37 (1H, d, J=7.5 Hz), 8.44 (1H, dd, J=4.8, 1.8 Hz),10.19 (1H, s).

Intermediate 61 9H-fluoren-9-ylmethylN-({2-[(3-formylpyridin-2-yl)sulfanyl]-3,5-bis(trifluoromethyl)phenyl}methyl)carbamate

To a stirred solution of 1-fluoro-2,4-bis(trifluoromethyl)benzene (3 g,12.9 mmol), TMEDA (2.3 mL, 15.5 mmol) in THF (30 mL) was added nBuLi(2.2M in THF, 6.4 mL, 14.2 mmol) at −78 deg C. and reaction mass wasstirred at −78° C. for 1 h. Then 1-formylpiperidine (2.2 mL, 19.4 mmol)was added to the reaction mass at −78° C. and it was stirred at −78° C.for 1 h and then at 25° C. for 1 h. Reaction mass was quenched withsaturated ammonium chloride solution and extracted with pentane. Theseparated organic layer was washed with brine solution, dried overanhydrous sodium sulfate and evaporated under reduced pressure to get2-fluoro-3,5-bis(trifluoromethyl) benzaldehyde (2.2 g).

To a stirred solution of 2-mercapto nicotinic acid (3.9 g, 25.4 mmol) inDMF (50 mL) was added NaH (60%, 1.8 g, 46.1 mmol) and reaction mass wasstirred at 25° C. for 30 min. Then2-fluoro-3,5-bis(trifluoromethyl)benzaldehyde (6 g, 23.1 mmol) was addedand reaction mixture was stirred at 70° C. for 4 h. Then K₂CO₃ (9.6 g,69.2 mmol) was added followed by addition of MeI (4.3 mL, 69.2 mmol) andreaction mass was stirred at 25° C. for 16 h. Reaction mass was quenchedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 0-8% ethyl acetate in hexane to get methyl2-{[2-formyl-4,6-bis(trifluoromethyl)phenyl]sulfanyl}pyridine-3-carboxylate(1.4 g, 11%, 2 steps) as a yellow solid. LC-MS: 409.5.

To a stirred solution of methyl2-{[2-formyl-4,6-bis(trifluoromethyl)phenyl]sulfanyl}pyridine-3-carboxylate(1.4 g, 3.4 mmol) in THF (10 mL) were added2-methylpropane-2-sulfinamide (415 mg, 3.4 mol), Ti(OEt)₄ (3.6 mL, 17.1mmol) and reaction mass was heated to 70° C. for 1 h. The reaction masswas quenched with saturated sodium chloride solution. The solid obtainedwas filtered through celite pad and washed with ethyl acetate. Theseparated organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford ethyl2-({2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-4,6-bis(trifluoromethyl)phenyl}sulfanyl)pyridine-3-carboxylate (1.6 g, crude) which was directly used for nextstep without further purification. LC-MS: 527.1 [M+H]⁺.

To a stirred solution of ethyl2-({2-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-4,6-bis(trifluoromethyl)phenyl}sulfanyl)pyridine-3-carboxylate (1.5 g, 2.8 mmol) in THF (15 mL) was added LAH(2M in THF, 2.13 mL, 4.3 mmol) at 0° C. and reaction mass was stirred at0° C. for 2 h. Reaction mixture was quenched with saturated sodiumsulfate solution and extracted with ethyl acetate. The separated organiclayer was washed with water, brine solution, dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The crude thus obtainedwas purified by normal silica column using 5-60% ethyl acetate in hexaneto getN-[(2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3,5-bis(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(800 mg, 48%, 2 steps) as off-white solid. LC-MS: 486.7 [M+H]⁺.

To a stirred solution ofN-[(2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3,5-bis(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(800 mg, 1.6 mmol) in MeOH (8 mL), was added 4M HCl in dioxan (4 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-4,6-bis(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (650 mg, crude) which was directly used for next step. LC-MS:382.8 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-4,6-bis(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (650 mg, 1.6 mmol) in 5% NaHCO₃ (100 mL) was added Fmoc-OSU(523 mg, 1.6 mmol) in acetonitrile (20 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine, dried over sodium sulfate andevaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-[(2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3,5-bis(trifluoromethyl)phenyl)methyl]carbamate(950 mg) as off white solid. LC-MS: 605.2 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-3,5-bis(trifluoromethyl)phenyl)methyl]carbamate(950 mg, 1.6 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂ (2.7 g, 31.46mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad. The filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({2-[(3-formylpyridin-2-yl)sulfanyl]-3,5-bis(trifluoromethyl)phenyl}methyl)carbamate (600 mg) as off white solid with 95% LCMS purity. LC-MS: 602.9[M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.22 (1H, d, J=6.8 Hz), 4.29 (4H, d, J=6.8Hz), 7.31 (2H, t, J=7.4 Hz), 7.41 (3H, t, J=6.0 Hz), 7.67 (2H, d, J=7.5Hz), 7.89 (2H, d, J=7.4 Hz), 7.94 (1H, s), 8.01 (1H, s), 8.12 (1H, s),8.41 (2H, d, J=7.2 Hz), 10.18 (1H, s).

Intermediate 62 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(morpholin-4-yl)phenyl}methyl)carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in toluene (10 mL) were added morpholine (272 mg, 3.1mmol) and sodium tertiary butoxide (675 mg, 7.0 mmol) and degassed inargon atmosphere for 5 min. Then to it were added 2-ditertiary butylphosphino biphenyl (70 mg, 0.2 mmol) and Pd(dba)₂ (120 mg, 0.21 mmol)and heated to 110° C. for 16 h. Reaction mass was filtered throughcelite pad and the filtrate was evaporated under reduced pressure. Thecrude thus obtained was purified by combiflash column chromatographyusing 20-80% ethyl acetate in hexane to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(morpholin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(530 mg) as brown sticky solid. LC-MS: 584.3 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(morpholin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(530 mg, 0.9 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(morpholin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (500 mg) which was directly used for next step. LC-MS: 365.8[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(morpholin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (500 mg, 1.4 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU (461mg, 1.4 mmol) in acetonitrile (10 mL) at 25° C. and reaction mass wasstirred at the same temperature for 16 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(morpholin-4-yl)phenyl)methyl]carbamate(530 mg) as off white solid. LC-MS: 588.2 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(morpholin-4-yl)phenyl)methyl]carbamate(530 mg, 0.90 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (1.18 g, 13.5mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad; filtrate was evaporated under reducedpressure. The crude material obtained was purified by columnchromatography using 30-80% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(morpholin-4-yl)phenyl}methyl)carbamate(230 mg, 42%, 3 steps) as off white solid. LC-MS: 585.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 3.19 (4H, s), 3.70 (4H, s), 4.18-4.28 (5H,m), 6.91 (1H, s), 7.07 (1H, s), 7.27-7.36 (3H, m), 7.41 (2H, d, J=7.2Hz), 7.69 (2H, d, J=6.9 Hz), 7.79 (1H, s), 7.90 (2H, d, J=7.7 Hz), 8.32(1H, d, J=6.5 Hz), 8.42 (1H, s), 10.20 (1H, s).

Intermediate 63 (9H-Fluoren-9-yl)methyl3-chloro-2-((3-formylpyrazin-2-yl)thio)-5-(trifluoromethyl)benzylcarbamate

A mixture of 3-mercaptopyrazine-2-carboxylic acid (1 g, 6.4 mmol, Eq:1), 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.45 g, 942 μl,6.4 mmol, Eq: 1) and K₂CO₃ (1.77 g, 12.8 mmol, Eq: 2) in DMF (10.7 ml)was stirred at 60° C. for 2 h. The reaction mixture was cooled to roomtemperature. Then iodomethane (4.54 g, 2 ml, 32 mmol, Eq: 5) was addedand stirring at room temperature continued for 2 h. The reaction mixturewas concentrated in vacuo. The residue was treated with water andextracted with EtOAc. The organic layers were washed with water andbrine, dried over Na₂SO₄ and concentrated in vacuo. Methyl3-((2-chloro-6-formyl-4-(trifluoromethyl)phenyl)thio)pyrazine-2-carboxylatewas obtained as brown solid (1.84 g) and was used without furtherpurification. MS ESI (m/z): 377.0 [(M+H)⁺].

To a mixture of methyl3-((2-chloro-6-formyl-4-(trifluoromethyl)phenyl)thio)pyrazine-2-carboxylate(1.84 g, 4.88 mmol, Eq: 1), 2-methylpropane-2-sulfinamide (592 mg, 4.88mmol, Eq: 1) in THF (20.4 ml) was added titanium(IV) ethoxide (5.57 g,5.12 ml, 24.4 mmol, Eq: 5). The reaction mixture was heated to 70° C.and stirred for 2 h. The mixture was quenched with brine, filteredthrough glass fiber paper and washed multiple times with EtOAc. Theorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. Ethyl3-((2-(((tert-butylsulfinyl)imino)methyl)-6-chloro-4-(trifluoromethyl)phenyl)thio)pyrazine-2-carboxylatewas obtained as light brown solid (2.26 g) and was used without furtherpurification. MS ESI (m/z): 494.2 [(M+H)⁺].

To a mixture of ethyl3-((2-(((tert-butylsulfinyl)imino)methyl)-6-chloro-4-(trifluoromethyl)phenyl)thio)pyrazine-2-carboxylate(2.2 g, 3.56 mmol, Eq: 1) and calcium chloride (1.38 g, 12.5 mmol, Eq:3.5) in ethanol (14.8 ml) and THF (20.8 ml) was added NaBH₄ (607 mg, 16mmol, Eq: 4.5) at 0° C. reaction mixture stirred at 0° C. for 1 h, thenat room temperature for 1 h. The mixture was quenched at 0° C. with sat.aq. NH₄Cl slt., extracted with ethyl acetate and the organic layerswashed with water. The combined organic layers were dried with Na₂SO₄,filtered and concentrated in vacuo.N-(3-chloro-2-((3-(hydroxymethyl)pyrazin-2-yl)thio)-5-(trifluoromethyl)benzyl)-2-methylpropane-2-sulfinamidewas obtained as light brown foam (2.0 g) and was used without furtherpurification. MS ESI (m/z): 454.2 [(M+H)⁺].

To a mixture ofN-(3-chloro-2-((3-(hydroxymethyl)pyrazin-2-yl)thio)-5-(trifluoromethyl)benzyl)-2-methylpropane-2-sulfinamide(2 g, 3.52 mmol, Eq: 1) in MeOH (17.6 ml) was added 4M HCl in dioxane(8.81 ml, 35.2 mmol, Eq: 10) and the reaction mixture stirred at roomtemperature for 2 h. The reaction mixture was concentrated in vacuo.(3-((2-(Aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)methanolhydrochloride was obtained as dark brown foam (2.3 g) and was usedwithout further purification. MS ESI (m/z): 350.1 [(M+H)⁺].

To a mixture of(3-((2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)methanolhydrochloride (2.3 g, 3.57 mmol, Eq: 1) and sodium bicarbonate (600 mg,7.15 mmol, Eq: 2) in acetonitrile (11.9 ml) and water (11.9 ml) wasadded Fmoc-OSu (1.21 g, 3.57 mmol, Eq: 1). The reaction mixture wasstirred at room temperature for 1 h. Again Fmoc-OSu (120 mg, 0.1 eq) wasadded and the mixture stirred for another 1 h. The mixture was thendiluted with EtOAc and water, extracted with ethyl acetate and theorganic layers washed with water. The combined organic layers were driedwith Na₂SO₄, filtered and concentrated in vacuo. (9H-Fluoren-9-yl)methyl3-chloro-2-((3-(hydroxymethyl)pyrazin-2-yl)thio)-5-(trifluoromethyl)benzylcarbamatewas obtained as yellow foam (2.7 g) and was used without furtherpurification. MS ESI (m/z): 572.2 [(M+H)⁺].

To a solution of (9H-fluoren-9-yl)methyl3-chloro-2-((3-(hydroxymethyl)pyrazin-2-yl)thio)-5-(trifluoromethyl)benzylcarbamate(2.7 g, 3.54 mmol, Eq: 1) in DCM (50.6 ml) was added dess-martinperiodinane (1.8 g, 4.25 mmol, Eq: 1.2) at 0° C. The cooling bath wasremoved and the mixture stirred 30 min at room temperature. The mixturewas diluted with sat. aq. NaHCO₃ slt. and extracted with EtOAc. Theorganic layers were washed with sat. aq. Na₂S₂O₃ slt. combined, driedover Na₂SO₄ and concentrated in vacuo. The crude material was purifiedby silica gel chromatography using heptane/EtOAc as eluent. The obtainedmaterial was triturated with EtOAc. The title compound(9H-fluoren-9-yl)methyl3-chloro-2-((3-formylpyrazin-2-yl)thio)-5-(trifluoromethyl)benzylcarbamatewas obtained as light yellow solid (1.02 g). MS ESI (m/z): 570.2[(M+H)⁺].

Intermediate 64 (9H-Fluoren-9-yl)methyl3-chloro-2-((3-formylpyrazin-2-yl)thio)-6-(trifluoromethyl)benzylcarbamate

This material was prepared in analogy to Intermediate 63 starting from3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde and3-mercaptopyrazine-2-carboxylic acid. The title compound was obtained aslight yellow foam (0.454 g). MS ESI (m/z): 570.2 [(M+H)⁺].

Intermediate 65 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridin-3-yl) phenyl}methyl)carbamate

To a stirred solution of 2-mercapto nicotinic acid (10.8 g, 69.5 mmol)in DMF (150 mL) was added NaH (60%, 5.1 g, 126.3 mmol) and reaction masswas stirred at 25° C. for 30 min. Then5-bromo-3-chloro-2-fluoro-benzaldehyde (15 g, 63.2 mmol) was added andreaction mixture was stirred at 70° C. for 4 h. Then K₂CO₃ (26.2 g,189.5 mmol) was added followed by addition of MeI (11.8 mL, 189.58 mmol)and reaction mass was stirred at 25° C. for 16 h. Reaction mass wasquenched with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude materialobtained was purified by normal silica column using 0-8% ethyl acetatein hexane to get methyl2-[(4-bromo-2-chloro-6-formylphenyl)sulfanyl]pyridine-3-carboxylate (12g, 49%) as a yellow solid.

To a stirred solution of methyl2-[(4-bromo-2-chloro-6-formylphenyl)sulfanyl]pyridine-3-carboxylate (15g, 38.9 mmol) in THF (80 mL) were added 2-methylpropane-2-sulfinamide(4.7 g, 38.9 mmol), Ti(OEt)₄ (40.7 mL, 194.3 mmol) and reaction mass washeated to 70° C. for 2 h. The reaction mass was quenched with saturatedsodium chloride solution, solid obtained was filtered through celite padand washed with ethyl acetate. The separated organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford ethyl2-({4-bromo-2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate(17 g) which was directly used for next step without furtherpurification. LC-MS: 502.7 [M+H]⁺.

To a stirred solution of ethyl2-({4-bromo-2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate(17 g, 33.8 mmol) in THF (80 mL) was added LAH (2M in THF, 25.3 mL, 50.7mmol) at 0° C. and reaction mass was stirred at 0° C. for 1 h. Reactionmixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to getN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(16 g) as off-white solid. LC-MS: 464.8 [M+H]⁺.

To a stirred solution of compoundN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(6 g, 12.9 mmol) in DCM (60 mL) were added imidazole (2.6 g, 38.8 mmol)and TBDMSCl (2.9 g, 19.4 mmol) at 0° C. and stirred at 25° C. for 3 h.Reaction mass was quenched with aq NaHCO₃ solution and extracted withethyl acetate. The separated organic layer was washed with water, brine,dried over sodium sulfate and evaporated under reduced pressure. Thecrude thus obtained was purified by combiflash column chromatographyusing 5-20% ethyl acetate in hexane to getN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(6 g, 69%) as off white solid. LC-MS: 578.8 [M+H]⁺.

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 3.5 mmol) in dioxan (20 mL) were added pyridine-3-boronic acid(553 mg, 4.5 mmol), Na₂CO₃ (1.1 g, 10.4 mmol), water (10 mL) anddegassed for 10 min in argon atmosphere. Then to it was addedPd(PPh₃)₄(200 mg, 0.17 mmol) and again degassed for 5 min. The reactionmass was heated to 120° C. for 16 h. Reaction mixture was then cooled to25° C., filtered through celite pad, washed with EtOAc. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand concentrated under vacuum to get the crude which was purified bynormal silica column using 5-80% ethyl acetate in hexane to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.3 g, 65%) as yellow solid. LC-MS: 576.2 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.3 g, 2.2 mmol) in MeOH (20 mL), was added 4M HCl in dioxan (10 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyridin-3-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (900 mg, crude) which was directly used for next step. LC-MS:358.0 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(pyridin-3-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (900 mg, 2.3 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (769mg, 2.3 mmol) in acetonitrile (30 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine, dried over sodium sulfate and evaporated underreduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridin-3-yl)phenyl) methyl]carbamate (1.2 g, crude) as off white solid. LC-MS: 580.0[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridin-3-yl)phenyl) methyl]carbamate (1.2 g, 2.1 mmol) in DCM:THF (1:1, 40 mL) wasadded MnO₂ (3.6 g, 41.4 mmol) and reaction mass was stirred at 25° C.for 2 h. The reaction mass was filtered through celite pad; filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridin-3-yl)phenyl}methyl)carbamate (700 mg, 53%, 3 steps) as off white solid with93.6% purity. LC-MS: 577.9 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.21 (1H, d, J=7.0 Hz), 4.28 (2H, d, J=6.9Hz), 4.37 (2H, d, J=5.5 Hz), 7.25 (2H, t, J=7.4 Hz), 7.33-7.44 (3H, m),7.55 (1H, dd, J=7.7, 4.9 Hz), 7.67 (2H, d, J=7.6 Hz), 7.73 (1H, s), 7.87(2H, d, J=7.8 Hz), 7.96 (1H, s), 8.15 (1H, d, J=7.2 Hz), 8.38 (1H, d,J=6.7 Hz), 8.45 (1H, d, J=3.3 Hz), 8.67 (1H, d, J=3.9 Hz), 8.98 (1H, s),10.22 (1H, s).

Intermediate 66 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridin-4-yl) phenyl}methyl)carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 3.5 mmol) in dioxan (20 mL) were added pyridine-4-boronic acid(553 mg, 4.5 mmol), Na₂CO₃ (1.1 g, 10.4 mmol), water (10 mL) anddegassed for 10 min in argon atmosphere. Then to it was addedPd(PPh₃)₄(200 mg, 0.17 mmol) and again degassed for 5 min. The reactionmass was heated to 120° C. for 16 h. Reaction mixture was then cooled to25° C., filtered through celite pad, washed with EtOAc. The separatedorganic layer was washed with brine, dried over sodium sulfate andconcentrated under vacuum to get the crude which was purified by normalsilica column using 5-80% ethyl acetate in hexane to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 60%) as yellow solid. LC-MS: 576.1 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 2.1 mmol) in MeOH (20 mL), was added 4M HCl in dioxan (10 mL) at0° C. and reaction mixture was stirred at 25° C. for 1 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (850 mg, crude) which was directly used for next step. LC-MS:357.8 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(pyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (850 mg, 2.1 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (726mg, 2.1 mmol) in acetonitrile (30 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine, dried over sodium sulfate and evaporated underreduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridin-4-yl)phenyl) methyl]carbamate (1.1 g, crude) as off white solid. LC-MS: 579.9[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridin-4-yl)phenyl) methyl]carbamate (1.1 g, 1.9 mmol) in DCM:THF (1:1, 40 mL) wasadded MnO₂ (3.3 g, 37.9 mmol) and reaction mass was stirred at 25° C.for 2 h. The reaction mass was filtered through celite pad; filtrate wasevaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 5-20% ethyl acetate in hexane toget 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridin-4-yl)phenyl}methyl) carbamate (650 mg) as off white solid with 95% LCMSpurity. LC-MS: 578.0 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.16-4.25 (1H, m), 4.28 (2H, d, J=6.5 Hz),4.34-4.40 (2H, m), 7.26 (2H, t, J=7.4 Hz), 7.39 (3H, t, J=7.3 Hz), 7.67(2H, d, J=7.3 Hz), 7.75 (3H, d, J=5.3 Hz), 7.88 (2H, d, J=7.4 Hz), 8.01(1H, s), 8.38 (1H, d, J=6.9 Hz), 8.44 (1H, d, J=4.6 Hz), 8.69 (2H, d,J=5.6 Hz), 10.22 (1H, s).

Intermediate 67 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(2-methoxypyridin-4-yl)phenyl}methyl)carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (10 mL) were added(2-methoxypyridin-4-yl)boronic acid (516 mg, 3.4 mmol), Na₂CO₃ (825 mg,7.8 mmol), water (5 mL) and degassed for 10 min in argon atmosphere.Then to it was added Pd(PPh₃)₄(150 mg, 0.13 mmol) and again degassed for5 min. The reaction mass was heated to 120° C. for 16 h. Reactionmixture was then cooled to 25° C., filtered through celite pad andwashed with EtOAc. The separated organic layer was washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-methoxypyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (1.5 g) as yellow solid.LC-MS: 605.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-methoxypyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (1.5 g, 2.5 mmol) in MeOH(30 mL), was added 4M HCl in dioxan (15 mL) at 0° C. and reactionmixture was stirred at 25° C. for 2 h. Reaction mass was evaporatedunder reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(2-methoxypyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (950 mg) which was directly used for next step. LC-MS: 388.8[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(2-methoxypyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (950 mg, 2.2 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (754mg, 2.2 mmol) in acetonitrile (30 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(2-methoxypyridin-4-yl)phenyl)methyl]carbamate(1.3 g) as off white solid. LC-MS: 609.9 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(2-methoxypyridin-4-yl)phenyl)methyl]carbamate(1.3 g, 2.1 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (3.7 g, 42.6mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 5-20% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(2-methoxypyridin-4-yl)phenyl}methyl)carbamate(650 mg) as off white solid with 96.9% LCMS purity. LC-MS: 608 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 3.92 (3H, s), 4.21 (1H, d, J=6.3 Hz), 4.27(2H, d, J=6.7 Hz), 4.36 (2H, d, J=5.8 Hz), 7.20 (1H, s), 7.26 (2H, t,J=7.3 Hz), 7.37 (4H, dd, J=16.2, 7.0 Hz), 7.67 (2H, d, J=7.3 Hz), 7.76(1H, s), 7.84-7.93 (3H, m), 7.98 (1H, s), 8.28 (1H, d, J=5.3 Hz), 8.38(1H, d, J=7.8 Hz), 8.44 (1H, d, J=5.6 Hz), 10.21 (1H, s).

Intermediate 68 (9H-Fluoren-9-yl)methyl3,6-dichloro-2-((2-formylpyridin-3-yl)thio)benzylcarbamate

This material was prepared in analogy to Intermediate 63 starting from3,6-dichloro-2-fluorobenzaldehyde and 3-mercaptopicolinic acid up to thesecond last step. Last step: A mixture of (9H-fluoren-9-yl)methyl3,6-dichloro-2-((2-(hydroxymethyl)pyridin-3-yl)thio)benzylcarbamate (18mg, 33.5 μmol, Eq: 1) and manganese dioxide (58.2 mg, 670 μmol, Eq: 20)in THF (335 μl) and DCM (335 μl) was stirred at room temperature for 1h. The resulting mixture was filtered through glass fiber paper andwashed with DCM. The filtrate was concentrated in vacuo. The titlecompound was obtained as white solid. MS ESI (m/z): 535.2 [(M+H)⁺].

Intermediate 69 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(2-methylpyridin-4-yl)phenyl} methyl) carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (10 mL) were added(2-methylpyridin-4-yl)boronic acid (462 mg, 3.4 mmol), Na₂CO₃ (825 mg,7.8 mmol), water (5 mL) and degassed for 10 min in argon atmosphere.Then it was added Pd(PPh₃)₄(150 mg, 0.13 mmol) and again degassed for 5min. The reaction mass was heated to 120° C. for 16 h. Reaction mixturewas then cooled to 25° C., filtered through celite pad and washed withEtOAc. The separated organic layer was washed with brine, dried oversodium sulfate and concentrated under reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-methylpyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, crude) as yellow solid. LC-MS: 589.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-methylpyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.5 mmol) in MeOH (30 mL), was added 4M HCl in dioxan (15 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(2-methylpyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (940 mg) which was directly used for next step. LC-MS: 371.8[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(2-methylpyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (940 mg, 2.3 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (776mg, 2.2 mmol) in acetonitrile (30 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(2-methylpyridin-4-yl)phenyl)methyl]carbamate(1.3 g, crude) as off white solid. LC-MS: 593.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(2-methylpyridin-4-yl)phenyl)methyl]carbamate(1.3 g, 2.19 mmol) in DCM/THF (1:1, 40 mL) was added MnO₂ (3.8 g, 43.8mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad; filtrate was evaporated under reducedpressure. The crude thus obtained was purified by normal silica columnusing 5-20% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(2-methylpyridin-4-yl)phenyl}methyl) carbamate (600 mg) as off white solid with 86% LCMSpurity. LC-MS: 592.0 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 2.50 (3H, s), 4.21 (1H, d, J=6.7 Hz), 4.28(2H, d, J=6.6 Hz), 4.37 (2H, d, J=5.1 Hz), 7.25 (2H, t, J=7.5 Hz),7.34-7.43 (3H, m), 7.50-7.60 (3H, m), 7.57-7.71 (6H, m), 7.76 (1H, s),7.84-7.95 (3H, m), 7.98 (1H, s), 8.39 (1H, d, J=7.5 Hz), 8.44 (1H, d,J=3.3 Hz), 8.55 (1H, d, J=5.2 Hz), 10.22 (1H, s).

Intermediate 70 9H-fluoren-9-ylmethylN-{[5-(6-{[(tert-butoxy)carbonyl]amino}pyridin-3-yl)-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide (600 mg, 1.0 mmol) in dioxan (5mL) were added 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(296 mg, 1.3 mmol), Na₂CO₃ (330 mg, 3.1 mmol), water (2.5 mL) anddegassed for 10 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(60 mg, 0.05 mmol) and again degassed for 5 min. The reaction mass washeated to 120° C. for 16 h. Reaction mixture was then cooled to 25° C.,filtered through celite pad and washed with EtOAc. The separated organiclayer was washed with brine, dried over sodium sulfate and concentratedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 10-70% ethyl acetate in hexane to getN-{[5-(6-aminopyridin-3-yl)-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl]methyl)-2-methylpropane-2-sulfinamide(500 mg) as yellow solid. LC-MS: 590.8 [M+H]⁺.

To a stirred solution ofN-{[5-(6-aminopyridin-3-yl)-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl]methyl)-2-methylpropane-2-sulfinamide(500 mg, 1.1 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-4-(6-aminopyridin-3-yl)-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (450 mg) which was directly used for next step. LC-MS: 372.8[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-4-(6-aminopyridin-3-yl)-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (450 mg, 1.1 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU (370mg, 1.1 mmol) in acetonitrile (15 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-{[5-(6-aminopyridin-3-yl)-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(600 mg) as off white solid. LC-MS: 594.9 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[5-(6-aminopyridin-3-yl)-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(550 mg, 0.9 mmol) in tertiary butanol (30 mL) was added boc anhydride(242 mg, 1.1 mmol) and reaction mass was stirred at 25° C. for 16 h.Reaction mass was evaporated under reduced pressure and crude thusobtained was purified by normal silica column using 5-40% ethyl acetatein hexane to get 9H-fluoren-9-ylmethylN-{[5-(6-{[(tert-butoxy)carbonyl]amino}pyridin-3-yl)-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(330 mg) as yellow solid. LC-MS: 695.2 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[5-(6-{[(tert-butoxy)carbonyl]amino}pyridin-3-yl)-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(350 mg, 0.50 mmol) in DCM:THF (1:1, 10 mL) was added MnO₂ (875 mg, 10.1mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 5-30% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-{[5-(6-{[(tert-butoxy)carbonyl]amino}pyridin-3-yl)-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate(220 mg, 63%) as off white solid with 94.7% LCMS purity. LC-MS: 693.1[M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 1.50 (9H, s), 4.21 (1H, d, J=6.9 Hz), 4.27(2H, d, J=7.7 Hz), 4.35 (2H, d, J=5.3 Hz), 7.27 (2H, t, J=7.8 Hz), 7.38(3H, t, J=7.1 Hz), 7.67 (3H, d, J=7.8 Hz), 7.85-7.92 (5H, m), 8.11 (1H,d, J=9.5 Hz), 8.33-8.41 (1H, m), 8.44 (1H, d, J=4.2 Hz), 8.66 (1H, s),10.02 (1H, s), 10.21 (1H, s).

Intermediate 71 (9H-Fluoren-9-yl)methyl3,6-dichloro-2-((3-formylpyrazin-2-yl)thio)benzylcarbamate

This material was prepared in analogy to Intermediate 68 starting from3,6-dichloro-2-fluorobenzaldehyde and 3-mercaptopyrazine-2-carboxylicacid. The title compound was obtained as light yellow foam (500 mg). MSESI (m/z): 536.2 [(M+H)⁺].

Intermediate 72 (9H-Fluoren-9-yl)methyl3-chloro-2-((2-formylpyridin-3-yl)thio)-6-(trifluoromethyl)benzylcarbamate

This material was prepared in analogy to Intermediate 63 starting from3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde and3-mercaptopicolinic acid. The title compound was obtained as light brownsolid (618 mg). MS ESI (m/z): 569.1 [(M+H)⁺].

Intermediate 73 (9H-Fluoren-9-yl)methyl3-chloro-2-((2-formylpyridin-3-yl)thio)-5-(trifluoromethyl)benzylcarbamate

This material was prepared in analogy to Intermediate 63 starting from3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde and3-mercaptopicolinic acid. The title compound was obtained as brown solid(183 mg). MS ESI (m/z): 569.1 [(M+H)⁺].

Intermediate 74 (9H-Fluoren-9-yl)methyl((2-chloro-3-((2-formylphenyl)thio)pyridin-4-yl)methyl)carbamate

To a mixture of 2-mercaptobenzoate (2 g, 1.64 ml, 11.5 mmol, Eq: 1) inDMF (19.2 ml) were added 2-chloro-3-fluoroisonicotinaldehyde (1.86 g,11.6 mmol, Eq: 1.01) und K₂CO₃ (3.17 g, 23 mmol, Eq: 1.99) and themixture stirred at room temperature over night. The reaction mixture wasdiluted with water and extracted with EtOAc. The organic layers werewashed with brine, combined, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified by silica gelchromatography using heptane/EtOAc as solvent. Methyl2-((2-chloro-4-formylpyridin-3-yl)thio)benzoate was obtained as yellowsolid (2.12 g) and used without further purification. MS ESI (m/z):308.1 [(M+H)⁺].

A mixture of methyl 2-((2-chloro-4-formylpyridin-3-yl)thio)benzoate(1.28 g, 4.16 mmol, Eq: 1), sodium acetate (478 mg, 5.82 mmol, Eq: 1.4)and hydroxylamine hydrochloride (376 mg, 5.41 mmol, Eq: 1.3) in aceticacid (16.6 ml) was stirred at room temperature for 30 min. Then zinc(1.36 g, 20.8 mmol, Eq: 5) was added and the reaction mixture wasstirred at room temperature for 30 min. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layers weredried over Na₂SO₄ and concentrated in vacuo. Methyl2-((4-(aminomethyl)-2-chloropyridin-3-yl)thio)benzoate was obtained aswhite solid (935 mg) and was used without further purification. MS ESI(m/z): 309.1 [(M+H)⁺].

To a mixture of methyl2-((4-(aminomethyl)-2-chloropyridin-3-yl)thio)benzoate (1 g, 3.24 mmol,Eq: 1) and sodium bicarbonate (1.36 g, 16.2 mmol, Eq: 5) in THF (10.8ml) and water (10.8 ml) was added Fmoc-OSu (1.09 g, 3.24 mmol, Eq: 1)and the reaction mixture stirred at room temperature for 2 h. Thereaction mixture was filtered through sintered glass and washed withdiisopropylether, the solid collected and dried. Methyl2-((4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-2-chloropyridin-3-yl)thio)benzoatewas obtained as white solid (1.9 g) and was used without furtherpurification. MS ESI (m/z): 531.2 [(M+H)⁺].

To a suspension of methyl2-((4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-2-chloropyridin-3-yl)thio)benzoate(1.9 g, 3.58 mmol, Eq: 1) in tetrahydrofuran (24.6 ml) was added LiBH₄(390 mg, 17.9 mmol, Eq: 5) and the reaction mixture was stirred at roomtemperature for 5 h. The reaction was quenched with sat. aq. NH₄Cl sltand diluted with water. The mixture was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by silica gel chromatographyusing heptane/EtOAc as eluent. (9H-fluoren-9-yl)methyl((2-chloro-3-((2-(hydroxymethyl)phenyl)thio)pyridin-4-yl)methyl)carbamatewas obtained as white foam (716 mg) and was used without furtherpurification. MS ESI (m/z): 503.2 [(M+H)⁺].

A mixture of (9H-fluoren-9-yl)methyl((2-chloro-3-((2-(hydroxymethyl)phenyl)thio)pyridin-4-yl)methyl)carbamate(280 mg, 557 μmol, Eq: 1) and manganese dioxide (484 mg, 5.57 mmol, Eq:10) in THF (3.98 ml) and DCM (3.98 ml) was stirred at room temperaturefor 3 h. The reaction mixture was filtered through sintered glass andconcentrated in vacuo. The title compound was obtained as white solid(265 mg). MS ESI (m/z): 501.2 [(M+H)⁺].

Intermediate 75 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl}methyl)carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (10 mL) were added[2-(4-methylpiperazin-1-yl)pyridin-4-yl]boronic acid (746 mg, 3.4 mmol),Na₂CO₃ (825 mg, 7.8 mmol), water (5 mL) and degassed for 10 min in argonatmosphere. Then it was added Pd(PPh₃)₄(150 mg, 0.13 mmol) and againdegassed for 5 min. The reaction mass was heated to 120° C. for 16 h.Reaction mixture was then cooled to 25° C., filtered through celite padand washed with ethyl acetate. The separated organic layer was washedwith brine, dried over sodium sulfate and concentrated under reducedpressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl}methyl)-2-methylpropane-2-sulfinamide(1.6 g) as yellow solid. LC-MS: 674.1 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl}methyl)-2-methylpropane-2-sulfinamide(1.6 g, 2.4 mmol) in MeOH (30 mL), was added 4M HCl in dioxan (15 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl]sulfanyl}pyridin-3-yl)methanol HCl salt (1 g) which was directly used for next step. LC-MS:456.1 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl]sulfanyl}pyridin-3-yl)methanol HCl salt (1 g, 2.0 mmol) in 5% NaHCO₃ (20 mL) was addedFmoc-OSU (685 mg, 2.0 mmol) in acetonitrile (30 mL) at 25° C. andreaction mass was stirred at the same temperature for 2 h. Then reactionmass was diluted with water and extracted with ethyl acetate. Theseparated organic layer was washed with brine solution, dried oversodium sulfate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl)methyl]carbamate(1.3 g) as off white solid. LC-MS: 678.1 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl)methyl]carbamate(1.0 g, 1.5 mmol) in DCM:THF (1:1, 20 mL) was added MnO₂ (2.5 g, 29.5mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 0-5% methanol in DCM to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]phenyl}methyl)carbamate(600 mg) as off white solid with 96.5% purity. LC-MS: 675.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 2.22 (3H, s), 2.39 (4H, s), 3.56 (4H, s),4.26 (3H, d, J=6.0 Hz), 4.36 (2H, d, J=4.9 Hz), 6.95 (1H, d, J=5.4 Hz),7.11 (1H, s), 7.26 (2H, t, J=5.9 Hz), 7.34-7.42 (3H, m), 7.67 (2H, d,J=7.3 Hz), 7.72 (1H, s), 7.88 (3H, d, J=7.8 Hz), 7.98 (1H, s), 8.20 (1H,d, J=4.9 Hz), 8.38 (1H, d, J=6.9 Hz), 8.44 (1H, d, J=2.8 Hz), 10.22 (1H,s).

Intermediate 763-chloro-5-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-4-[(3-formylpyridin-2-yl)sulfanyl]phenyl]boronic acid

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (12.0 ml) were added bispinacolate diborane(1.6 g, 6.2 mmol) and potassium acetate (1.0 g, 10.4 mmol) and degassedin argon atmosphere for 5 min. Then to it was added PdCl2(dppf) (424 mg,0.52 mmol) and heated to 110° C. for 16 h. Reaction mass was filteredthrough celite pad and the filtrate was evaporated under reducedpressure and the filtrate was then extracted with ethyl acetate. Theseparated organic layer was washed with brine solution, dried oversodium sulfate and evaporated under reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.6 g) which was directly used for next step. LC-MS: 625.3 [M+H]⁺.

To a stirred solutionN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.6 g, 2.6 mmol) in MeOH (24 mL), was added 4M HCl in dioxan (12 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanyl}pyridin-3-yl)methanol as HCl salt (1.6 g) which was directly used for next step.LC-MS: =407 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.6 g, 3.9 mmol) in 5% NaHCO₃ (25 mL) was added Fmoc OSU(1.329 g, 3.9 mmol) in acetonitrile (25 mL) at 25° C. and reaction masswas stirred at the same temperature for 16 h. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand evaporated under reduced pressure to 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl]carbamate (1.8 g) as brown sticky solid; which was used for nextstep without further purification. LC-MS: 629.1 [M+H].

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl]carbamate(1.0 g, 1.59 mmol) in DCM:THF (1:1, 20 mL) was added MnO₂ (3.74 g, 43mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by washing withethyl acetate to get[3-chloro-5-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-4-[(3-formylpyridin-2-yl)sulfanyl]phenyl]boronicacid (270 mg) as an off white sticky solid. LC-MS: 544.9 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 4.02-4.08 (2H, m), 4.15-4.22 (2H, m),4.28-4.29 (2H, m) 7.27-7.32 (4H, m), 7.39-7.40 (2H, m), 7.57-7.69 (2H,m), 7.80-7.81 (2H, m), 7.85-7.95 (2H, m); 8.20-8.40 (m; 2H); 10.19 (1H,s).

Intermediate 77 (9H-Fluoren-9-yl)methyl3-chloro-2-((4-formylpyridin-3-yl)thio)-6-(trifluoromethyl)benzylcarbamate

This material was prepared in analogy to Intermediate 63 starting from3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde and3-mercaptoisonicotinic acid hydrochloride. Only the reduction step wascarried out as follows:

To a solution of ethyl3-((2-(((tert-butylsulfinyl)imino)methyl)-6-chloro-3-(trifluoromethyl)phenyl)thio)isonicotinate(295 mg, 598 μmol, Eq: 1) in DCM (6 ml) was added dropwise 1M DIBAL-H inTHF (1.8 ml, 1.8 mmol, Eq: 3) at room temperature and stirred for 2 h.The reaction mixture was quenched at 0° C. with sat. aq. NH₄Cl slt.,diluted with water and extracted with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The titlecompound was obtained as light brown foam (183 mg). MS ESI (m/z): 569.1[(M+H)⁺].

Intermediate 78 (9H-Fluoren-9-yl)methyl3-chloro-2-((4-formylpyridin-3-yl)thio)-5-(trifluoromethyl)benzylcarbamate

This material was prepared in analogy to Intermediate 77 starting from3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde and3-mercaptoisonicotinic acid hydrochloride, except for the last stepwhich was done in analogy to RO7117947-000. The title compound wasobtained as white solid (110 mg). MS ESI (m/z): 569.1 [(M+H)⁺].

Intermediate 79 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-4-phenyl-phenyl]methyl]carbamate

To a stirred solution of 1-bromo-2-chloro-3-fluoro benzene (1.0 g, 4.79mmol) in toluene (20 mL) were added phenyl boronic acid (875 mg, 7.18mmol), Na2CO3 (1.52 g, 14.35 mmol), water (5 mL) and degassed for 10 minin argon atmosphere. Then to it was added Pd(PPh3)4 (553 mg, 0.48 mmol)and again degassed for 5 min. The reaction was heated to 100° C. for 16h. The reaction mixture was then cooled to 25° C., filtered throughcelite and washed with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to get the crude product which was purified bycombiflash column chromatography using hexane to get2-chloro-1-fluoro-3-phenylbenzene (920 mg, 93%) as yellow, stickyliquid.

To the stirred solution of 2-chloro-1-fluoro-3-phenylbenzene (4.0 g,19.42 mmol) in THF (25 ml) was added LDA (2M in THF, 14.4 mL) at −78° C.and reaction mass was stirred at the same condition for 1 h. Then to thereaction mixture was added DMF (5 mL) at −78° C. and stirred at roomtemperature for 2 h. The reaction was quenched with water and extractedwith ethyl acetate. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to get the crude product which was purified by silica columnchromatography using 0-10% ethyl acetate in hexane to get3-chloro-2-fluoro-4-phenylbenzaldehyde as light yellow solid (2.5 g,54%).

To a stirred solution of 2-mercapto nicotinic acid (3.6 g, 23.2 mmol) inDMF (30 mL) was added NaH (60%, 1.11 g, 46.4 mmol) and the reaction wasstirred at 25° C. for 30 min. Then3-chloro-2-fluoro-4-phenylbenzaldehyde (5.971 g, 25.519 mmol) was addedand the reaction mixture was stirred at 90° C. for 6 h. Then K₂CO₃ (9.62g, 69.6 mmol) was added followed by addition of methyliodide (4.33 ml,69.597 mmol) and the reaction was stirred at 25° C. for 16 h. TheReaction was quenched with water and extracted with ethyl acetate. Theseparated organic layer was washed with brine solution, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by normal silica column using 0-20% ethylacetate in hexane to get methyl2-[(2-chloro-6-formyl-3-phenylphenyl)sulfanyl]pyridine-3-carboxylate(4.5 g, 50%) as a sticky solid.

LC-MS: m/z=383.9 (M+H)⁺ for monoisotopic mass 383.04

To a stirred solution of methyl2-[(2-chloro-6-formyl-3-phenylphenyl)sulfanyl]pyridine-3-carboxylate(4.5 g, 11.75 mmol) in THF (40 mL) were added2-methylpropane-2-sulfinamide (1.42 g, 11.75 mmol), Ti(OEt)₄ (12.317 ml,58.747 mmol) and the reaction was heated to 70° C. for 45 min. Thereaction was quenched with saturated sodium chloride solution, theobtained solid was filtered through celite, washed with ethyl acetate.The separated organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford methyl2-({2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]-3-phenylphenyl}sulfanyl)pyridine-3-carboxylate(4.8 g, crude) which was directly used for next step without furtherpurification.

LC-MS: m/z=486.8 (M+H)⁺ for monoisotopic mass 486.08

To a stirred solution of methyl2-({2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]-3-phenylphenyl}sulfanyl)pyridine-3-carboxylate(4.8 g, 9.88 mmol) in THF (40 mL) was added LAH (2M in THF, 7.4 mL,14.81 mmol) at 0° C. and the reaction was stirred at 0° C. for 1 h. Thereaction mixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude obtained product waspurified by normal silica column using 50-90% ethyl acetate in hexane togetN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-4-phenylphenyl)methyl]-2-methylpropane-2-sulfinamide(4.0 g, 74% 2 steps) as off-white solid.

LC-MS: m/z=460.8 (M+H)⁺ for monoisotopic mass 460.10

To a stirred solution ofN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-4-phenylphenyl)methyl]-2-methylpropane-2-sulfinamide(4.0 g, 8.7 mmol) in MeOH (40 mL), was added 4M HCl in dioxane (20 mL)at 0° C. and the reaction mixture was stirred at 25° C. for 3 h. Thesolvent was evaporated under reduced pressure to yield(2-{[6-(aminomethyl)-2-chloro-3-phenylphenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (3.5 g, crude) which was directly used for next step. LC-MS:m/z=356.9 (M+H)⁺ for monoisotopic mass 356.08

To a stirred suspension of(2-{[6-(aminomethyl)-2-chloro-3-phenylphenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (3.5 g, 9.831 mmol) in 5% NaHCO₃ (25 mL) was added Fmoc OSU(3.32 g, 9.83 mmol) in CH₃CN (25 mL) at 25° C. and the reaction wasstirred at the same temperature for 16 h. Then the reaction was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-4-phenylphenyl)methyl]carbamate(3.7 g, crude) which was directly used for next step.

LC-MS: m/z=579.1 (M+H)⁺ for monoisotopic mass 578.14

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-4-phenylphenyl)methyl]carbamate(3.7 g, 6.40 mmol) in DCM/THF (1:1, 60 mL) was added MnO₂ (5.57 g, 64.01mmol) and the reaction was stirred at 25° C. for 1 h. The reaction wasfiltered through a pad of celite; the filtrate was evaporated underreduced pressure. The crude product was purified by normal silica columnusing 10-30% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-4-phenylphenyl}methyl)carbamate(3.5 g, 70%) as a off white solid.

LC-MS: m/z=577.0 (M+H)⁺ for monoisotopic mass 576.13

1H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.47 (d, 1H), 8.36 (d, 1H),7.89 (d, 2H), 7.69 (d, 2H), 7.51-7.31 (m, 12H), 4.33-4.29 (m, 4H), 4.22(m, 1H)

Intermediate 80 9H-fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-5-phenyl-3-(trifluoromethyl)phenyl]methyl]carbamate

To a stirred solution of 5-bromo-2-fluoro-3-trifluoromethylbenzaldehyde(4.63 g, 21.4 mmol) and methyl 2-sulfanylbenzoate (3.0 g, 17.9 mmol) inDMF (30 mL) was added K₂CO₃ (4.93 g, 35.7 mmol) and the reaction wasstirred at 25° C. for 1 h. Reaction mixture was diluted with ethylacetate and washed with water. The separated organic layer was washedwith sat. NaCl solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The obtained crude product waspurified by combiflash column chromatography using 10% EA/Hexane to getmethyl 2-{[4-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanyl}benzoate(6 g, 80%) as off white solid.

To a stirred solution of methyl 2-{[4-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanyl}benzoate (0.5 g, 1.19 mmol) in THF (5 mL) were added2-methylpropane-2-sulfinamide (288.6 mg, 2.38 mol), Ti(OEt)4 (0.75 mL,3.57 mmol) and reaction mass was heated to 70° C. for 2 h. The reactionwas quenched with saturated sodium chloride solution, the obtained solidwas filtered through celite, washed with ethyl acetate. The separatedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford ethyl2-({4-bromo-2-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]-6-(trifluoromethyl)phenyl}sulfanyl)benzoate (0.6 g, crude) which was directly used for nextstep without further purification.

LC-MS: mixture of methyl- and ethyl-ester, ratio ca. 3:1; m/z=522.2(M+H)+ for methyl ester (MW 520.99 for monoisotopic mass) and 536.2(M+H)+ for ethyl ester (MW 535.01 for monoisotopic mass).

To a stirred solution of ethyl2-({4-bromo-2-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]-6-(trifluoromethyl)phenyl}sulfanyl)benzoate (0.9 g, 1.724 mmol) in THF (20 mL) was addedLiAlH4(2M in THF, 1.7 mL, 3.44 mmol) at 0° C. and the reaction wasstirred at 0° C. for 1 h. Reaction mixture was quenched with saturatedsodium sulfate solution and extracted with ethyl acetate. The separatedorganic layer was washed with water, brine solution, dried overanhydrous sodium sulfate and evaporated under reduced pressure to getN-[[5-bromo-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(0.8 g, crude) which was directly used for next step without furtherpurification.

LC-MS: m/z=495.9 (M+H)⁺ for monoisotopic mass 495.01

To a stirred solution ofN-[[5-bromo-2-[2-(hydroxymethyl)phenyl]sulfanyl-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(1 g, 2 mmol) in DCM (30 mL) were added imidazole (0.41 g, 6 mmol) andTBDMSCl (0.455 g, 3. mmol) at 0° C. and stirred at 25° C. for 1 h.Reaction mass was quenched with aq NaHCO₃ solution and extracted withethyl acetate. The separated organic layer was washed with water, brinesolution, dried over sodium sulfate and evaporated under reducedpressure. The crude product was purified by normal silica gel columnchromatography using 10% ethyl acetate in hexane to getN-({5-bromo-2-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)sulfanyl]-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide (0.95 g, 77%) as colorlesssticky liquid.

LC-MS: m/z=611.8 (M+H)⁺ for monoisotopic mass 609.10

To a stirred solution ofN-({5-bromo-2-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)sulfanyl]-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide (5.5 g, 9.55 mmol) intoluene (88 mL) were added phenyl boronic acid (1.75 g, 14.3 mmol),Na2CO3 (3.03 g, 28.6 mmol), water (22 mL), the mixture was degassed for10 min under argon atmosphere. Then to it was added Pd(PPh3)4 (1.1 g,0.955 mmol) and again degassed for 5 min. The reaction mass was heatedto 110° C. for 16 h. Reaction mixture was then cooled to 25° C.,filtered through celite, washed with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand concentrated under reduced pressure. Crude product was purified bynormal silica gel column chromatography, eluted with 50% ethylacetate inhexane to get N-({2-[(2-{[(tert-butyldimethylsilyl) oxy]methyl}phenyl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide (4.7 g, 81%) as yellowsolid.

To a stirred solution ofN-({2-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide (1.5 g, 2.47 mmol) in MeOH(20 mL), was added 4M HCl in dioxane (6 mL) at 0° C. and reactionmixture was stirred at 25° C. for 2 h. The solvent was evaporated underreduced pressure to get(2-{[2-(aminomethyl)-4-phenyl-6-(trifluoromethyl)phenyl]sulfanyl}phenyl) methanol hydrochloride (1.1 g, crude) which wasdirectly used for next step.

LC-MS: m/z=390.2 (M+H)⁺ for monoisotopic mass 389.11

To a stirred suspension of(2-{[2-(aminomethyl)-4-phenyl-6-(trifluoromethyl)phenyl]sulfanyl}phenyl) methanol hydrochloride (3.5 g, 9 mmol) in 5%NaHCO₃ (250 mL) was added Fmoc N-hydroxysuccinimide ester (3.03 g, 9mmol) in CH3CN (70 mL) at 25° C. and reaction was stirred at the sametemperature for 16 h. Then the reaction was diluted with water andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over sodium sulfate and evaporated underreduced pressure to yield 9H-fluoren-9-ylmethylN-[[2-[2-(hydroxymethyl)phenyl]sulfanyl-5-phenyl-3-(trifluoromethyl)phenyl]methyl]carbamate(3.7 g, crude) which was directly used for next step.

LC-MS: m/z=594.3 (M+H-H2O)⁺ for monoisotopic mass 611.17

To a stirred solution of 9H-fluoren-9-ylmethyl N-[(2-{[2-(hydroxymethyl)phenyl]sulfanyl}-5-phenyl-3-(trifluoromethyl) phenyl) methyl]carbamate(3.5 g, 5.7 mmol) in DCM/THF (1:1, 160 mL) was added MnO2 (7.47 g, 85.9mmol) and the reaction was stirred at 25° C. for 1 h. The reactionmixture was filtered through celite; filtrate was evaporated underreduced pressure. The crude product was purified by normal silica columnusing 10% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({2-[(2-formylphenyl)sulfanyl]-5-phenyl-3-(trifluoromethyl)phenyl}methyl)carbamate (3.2 g, 91%) as off white solid.

LC-MS: m/z=592.4 (M+H-H2O)⁺ for monoisotopic mass 609.16

1H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1H), 8.11 (s, 1H), 8.03-7.93 (m,3H), 7.86 (d, 2H), 7.78 (d, 2H), 7.66 (d, 2H), 7.56-7.43 (m, 4H), 7.38(t, 3H), 7.23 (t, 2H), 6.50 (d, 1H), 4.33-4.26 (m, 4H), 4.20 (m, 1H).

Intermediate 81 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-phenylphenyl}methyl)carbamate

To a stirred solution ofN-[(6-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(8.9 g, 19.2 mmol) in DCM (50 mL) were added imidazole (3.9 g, 57.6mmol) and TBDMSCl (4.33 g, 28.8 mmol) at 0° C. and stirred at 25° C. for2 h. Reaction mass was quenched with aq NaHCO₃ solution and extractedwith ethyl acetate. The separated organic layer was washed with water,brine, dried over sodium sulfate and evaporated under reduced pressure.The crude thus obtained was purified by combiflash column chromatographyusing 0-20% ethyl acetate in hexane to getN-({6-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(9 g) as off white solid. LC-MS: 578.6 [M+H]⁺.

To a stirred solution of compoundN-({6-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (10 mL) were added phenyl boronic acid (411mg, 3.4 mmol), Na₂CO₃ (825 mg, 7.8 mmol), water (5 mL) and degassed for10 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(150 mg, 0.13mmol) and again degassed for 5 min. The reaction mass was heated to 120°C. for 16 h. Reaction mixture was then cooled to 25° C., filteredthrough celite pad, washed with EtOAc. The separated organic layer waswashed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-phenylphenyl}methyl)-2-methylpropane-2-sulfinamide(1.3 g) as yellow solid. LC-MS: 575.0 [M+H]⁺.

To a stirred solution of NN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-phenylphenyl}methyl)-2-methylpropane-2-sulfinamide(1.3 g, 2.26 mmol) in MeOH (20 mL), was added 4M HCl in dioxan (10 mL)at 0° C. and reaction mixture was stirred at 25° C. for 2 h. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-3-phenylphenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (890 mg, crude) which was directly used for next step.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-3-phenylphenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (890 mg, 2.3 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc OSU (762mg, 2.3 mmol) in acetonitrile (20 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-phenylphenyl)methyl]carbamate (1.2 g) as off white solid. LC-MS: 578.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-phenylphenyl)methyl]carbamate (1.2 g, 2.1 mmol) in DCM/THF (1:1, 40 mL) was addedMnO₂ (3.6 g, 41.4 mmol) and reaction mass was stirred at 25° C. for 2 h.The reaction mass was filtered through celite, filtrate was evaporatedunder reduced pressure to get crude mass that was purified by normalsilica column using 10-40% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-phenylphenyl}methyl)carbamate (710 mg) as off white solid with 98% purity. LC-MS: 576.8[M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.08-4.15 (5H, m), 7.34 (4H, q, J=7.3, 6.2Hz), 7.42 (7H, d, J=8.1 Hz), 7.58 (1H, s), 7.64-7.71 (3H, m), 7.89 (2H,d, J=7.5 Hz), 8.33 (1H, d, J=7.7 Hz), 8.48 (1H, d, J=3.2 Hz), 10.21 (1H,s).

Intermediate 82 9H-Fluoren-9-ylmethyl N-{[5-(3-{[(tert-butoxy) carbonyl]amino} pyrrolidin-1-yl)-3-chloro-2-[(3-formylpyridin-2-yl) sulfanyl]phenyl] methyl} carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(750 mg, 1.3 mmol) in toluene (7 mL) were added tert-butylpyrrolidine-3-carboxylate (290.5 mg, 1.5 mmol) and sodium tertiarybutoxide (337.3 mg, 3.5 mmol) and degassed in argon atmosphere for 5min. Then to it were added 2-ditertiary butyl phosphino biphenyl (34.9mg, 0.12 mmol) and Pd(dba)₂ (59.8 mg, 0.1 mmol) and heated to 110° C.for 16 h. Reaction mass was filtered through celite pad and the filtratewas evaporated under reduced pressure. The crude thus obtained waspurified by combiflash column chromatography using 60% ethylacetate inhexane to get tert-butylN-(1-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-{[(2-methylpropane-2-sulfinyl)amino]methyl}phenyl}pyrrolidin-3-yl)carbamate (450 mg) as off-whitesolid. LC-MS: 683.1 [M+H]⁺.

To a stirred solution of tert-butylN-(1-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-{[(2-methylpropane-2-sulfinyl)amino]methyl}phenyl}pyrrolidin-3-yl)carbamate (900 mg, 1.3 mmol) in THF (10 mL) was added TBAF in 1 (M) THF(1.9 mL) and reaction mixture was stirred at 25° C. for 1 h. Aftercompletion of reaction, reaction mixture was extracted with ethylacetate, washed with water, brine solution, dried over Na2SO4 andevaporated under reduced pressure to get tert-butylN-[1-(3-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-{[(2-methylpropane-2-sulfinyl)amino]methyl}phenyl)pyrrolidin-3-yl]carbamate(700 mg) which was directly used for next step. LC-MS: 568.6 [M+H]⁺.

To a stirred solution of tert-butylN-[1-(3-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-{[(2-methylpropane-2-sulfinyl)amino]methyl}phenyl)pyrrolidin-3-yl]carbamate(700 mg, 1.2 mmol) in MeOH (8 mL), was added 4M HCl in dioxan (4 mL) at0° C. and reaction mixture was stirred at 25° C. for 15 mins. Reactionmass was evaporated under reduced pressure to get tert-butylN-{1-[3-(amino methyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]pyrrolidin-3-yl}carbamate hydrochloride(600 mg) which was directly used for next step. LC-MS: 464.9 [M+H]⁺.

To a stirred suspension of tert-butylN-{1-[3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]pyrrolidin-3-yl}carbamateHClsalt (600 mg, 1.3 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU (436.0mg, 1.3 mmol) in dioxan (10 mL) at 25° C. and reaction mass was stirredat the same temperature for 2 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-Fluoren-9-ylmethylN-{[5-(3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl)-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate (700 mg) as off whitesolid; which was used for next step without further purification. LC-MS:687.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[5-(3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl)-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(700 mg, 1.02 mmol)) in DCM:THF (1:1, 20 mL) was added MnO₂ (1.8 g, 20.4mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 30%-80% ethylacetate in hexane to get9H-Fluoren-9-ylmethyl N-{[5-(3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl)-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate (250 mg) as off white solid with 96%LCMS purity. LC-MS: 685.1 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 1.40 (9H, s), 1.87-1.96 (1H, m), 2.14 (1H,dd, J=12.4, 7.0 Hz), 3.09 (1H, dd, J=8.4, 3.6 Hz), 3.26 (1H, dd, J=8.6,7.0 Hz), 3.34-3.42 (1H, m), 3.49 (1H, dd, J=9.6, 7.0 Hz), 4.24 (5H, dd,J=18.9, 6.4 Hz), 6.51 (1H, s), 6.60 (1H, s), 7.32 (4H, q, J=5.8 Hz),7.41 (2H, t, J=5.8 Hz), 7.68 (2H, d, J=7.1 Hz), 7.78 (1H, s), 7.89 (2H,d, J=7.2 Hz), 8.29 (1H, d, J=7.2 Hz), 8.42 (1H, d, J=3.7 Hz), 10.21 (1H,s).

Intermediate 83 9H-Fluoren-9-ylmethylN-{[3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl] phenyl] methyl} carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 2.1 mmol) in dioxan (10 mL) were added2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(567 mg, 2.7 mmol), Na₂CO₃ (660 mg, 6.2 mmol), water (5 mL) and degassedfor 10 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(120 mg,0.1 mmol) and again degassed for 5 min. The reaction mass was heated to120° C. for 16 h. Reaction mixture was then cooled to 25° C., filteredthrough celite pad and washed with ethyl acetate. The separated organiclayer was washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g) as yellow sticky solid; which was used for next step withoutfurther purification. LC-MS: 580.9 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 2.0 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get (2-{[2-(aminomethyl)-6-chloro-4-(3,6-dihydro-2H-pyran-4-yl) phenyl] sulfanyl}pyridin-3-yl) methanol hydrochloride (820 mg) which was directly usedfor next step. LC-MS: 362.8 [M+H]⁺.

To a stirred suspension of (2-{[2-(aminomethyl)-6-chloro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (820 mg, 2.0 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU(692 mg, 2.0 mmol) in acetonitrile (20 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand evaporated under reduced pressure to give 9H-Fluoren-9-ylmethylN-{[3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl] sulfanyl} phenyl] methyl} carbamate (1 g) as off whitesolid, which was used for next step without further purification. LC-MS:584.9 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(1.0 g, 1.7 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (2.97 g, 34.2mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 10%-40% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-{[3-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate(550 mg) as a off white solid with 94% LCMS purity. LC-MS: 582.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 2.39-2.48 (3H, m), 3.80 (2H, t, J=4.6 Hz),4.22 (3H, s), 4.27 (3H, d, J=6.7 Hz), 6.39 (1H, s), 7.31 (2H, t, J=7.0Hz), 7.37-7.47 (4H, m), 7.60 (1H, s), 7.69 (2H, d, J=7.5 Hz), 7.89 (3H,t, J=7.1 Hz), 8.36 (1H, d, J=7.6 Hz), 8.42 (1H, d, J=4.8 Hz), 10.20 (1H,s).

Intermediate 84 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyrazin-2-yl)phenyl}methyl)carbamate

To a stirred and degassed solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (12 mL) were added4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.6 g, 6.2 mmol) and potassium acetate (1.0 g, 10.4 mmol), PdCl₂dppf(424 mg, 0.52 mmol) and reaction mass was heated to 110° C. for 16 h.Reaction mass was filtered through celite pad and the filtrate wasevaporated under reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.6 g) which was directly used for next step. LC-MS: 625.3 [M+H]⁺.

To a stirred solution of 2-bromopyrazin (500 mg, 3.1 mmol) in dioxan (5mL) were addedN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.3 g, 3.7 mmol), Na₂CO₃ (1.0 g, 9.4 mmol), water (2 mL) and degassedfor 10 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(363 mg,0.31 mmol) and again degassed for 5 min. The reaction mass was heated to120° C. for 16 h. Reaction mixture was then cooled to 25° C., filteredthrough celite pad and washed with EtOAc. The separated organic layerwas washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure. The crude thus obtained waspurified by normal silica column using 0-10% methanol in DCM to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyrazin-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(450 mg) as off white solid. LC-MS: 577.1 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyrazin-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(450 mg, 0.781 mmol) in MeOH (8 mL), was added 4M HCl in dioxan (4 mL)at 0° C. and reaction mixture was stirred at 25° C. for 2 h. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyrazin-2-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (400 mg) which was directly used for next step. LC-MS: 358.9[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(pyrazin-2-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (400 mg, 1. mmol) in 5% NaHCO₃ (6 mL) was added Fmoc-OSU (376mg, 1.1 mmol) in dioxan (6 mL) at 25° C. and reaction mass was stirredat the same temperature for 2 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyrazin-2-yl)phenyl)methyl]carbamate(500 mg, crude) as off white solid. LC-MS: 581.1 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyrazin-2-yl)phenyl)methyl]carbamate(500 mg, 0.86 mmol) in DCM:THF (1:1, 20 mL) was added MnO₂ (1.49 g,17.24 mmol) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad and filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 10-80% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyrazin-2-yl)phenyl}methyl)carbamate(130 mg) as off white solid. LC-MS: 578.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.24-4.32 (3H, m), 4.34-4.41 (2H, m), 7.28(2H, t, J=6.9 Hz), 7.37-7.42 (3H, m), 7.69 (2H, d, J=7.7 Hz), 7.88 (2H,d, J=7.5 Hz), 7.92-8.00 (1H, m), 8.17-8.22 (1H, m), 8.28-8.34 (1H, m),8.35-8.42 (1H, m), 8.41-8.47 (1H, m), 8.68-8.75 (2H, m), 9.35 (1H, s),10.22 (1H, s).

Intermediate 85 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(morpholin-4-yl)phenyl}methyl)carbamate

To a stirred solution of 2-mercapto nicotinic acid (719 mg, 4.6 mmol) inDMF (10 mL) was added NaH (60%, 336 mg, 8.4 mmol) and reaction mass wasstirred at 25° C. for 30 min. Then6-Bromo-3-chloro-2-fluoro-benzaldehyde (1 g, 4.2 mmol) was added andreaction mixture was stirred at 90° C. for 4 h. Then K₂CO₃ (1.74 g, 12.6mmol) was added followed by addition of MeI (0.8 mL, 12.6 mmol) andreaction mass was stirred at 25° C. for 16 h. The reaction was quenchedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 5-15% ethyl acetate in hexane to getmethyl2-[(3-bromo-6-chloro-2-formylphenyl)sulfanyl]pyridine-3-carboxylate (800mg, 49%) as yellow solid. LC-MS: 388.0 [M+H]⁺.

To the stirred solution of compound methyl2-[(3-bromo-6-chloro-2-formylphenyl)sulfanyl]pyridine-3-carboxylate (1.3g, 3.4 mmol) in toluene (10 mL) were added Morpholine (352 mg, 4.0 mmol)and Cs₂CO₃ (2.9 g, 9.1 mmol) and degassed in argon atmosphere for 5 min.Then to it were added Xanthphos (175 mg, 0.3 mmol), Pd₂(dba)₃ (247 mg,0.27 mmol) and heated to 110° C. for 16 h. Reaction mass was filteredthrough celite pad and the filtrate was evaporated under reducedpressure. The crude thus obtained was purified by combiflash columnchromatography using 20-60% ethyl acetate in hexane to get the methyl2-{[6-chloro-2-formyl-3-(morpholin-4-yl)phenyl]sulfanyl}pyridine-3-carboxylate(260 mg) as brown sticky solid. LC-MS: 393.0 [M+H]⁺.

To a stirred solution of methyl2-{[6-chloro-2-formyl-3-(morpholin-4-yl)phenyl]sulfanyl}pyridine-3-carboxylate(550 mg, 1.4 mmol) in THF (10 mL) were added2-methylpropane-2-sulfinamide (170 mg, 1.40 mmol), Ti(OEt)₄ (1.5 mL, 7.0mmol) and reaction mass was heated to 70° C. for 45 min. The reactionmass was quenched with saturated sodium chloride solution, solidobtained was filtered through celite pad, washed with ethyl acetate. Theseparated organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford ethyl2-[(6-chloro-2-{[(2-methylpropane-2-sulfinyl)imino]methyl}-3-(morpholin-4-yl)phenyl)sulfanyl]pyridine-3-carboxylate(600 mg, crude) which was directly used for next step without furtherpurification. LC-MS: 509.6 [M+H]⁺.

To a stirred solution of2-[(6-chloro-2-{[(2-methylpropane-2-sulfinyl)imino]methyl}-3-(morpholin-4-yl)phenyl)sulfanyl]pyridine-3-carboxylate(600 mg, 1.2 mmol) in THF (30 mL) was added LAH (2M in THF, 1.2 mL, 2.3mmol) at 0° C. and reaction mass was stirred at 0° C. for 1 h. Reactionmixture was quenched with saturated sodium sulfate solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to getN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(morpholin-4-yl)phenyl)methyl]-2-methylpropane-2-sulfinamide(530 mg, crude) as of white solid. LC-MS: 469.6 [M+H]⁺.

To a stirred solution ofN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(morpholin-4-yl)phenyl)methyl]-2-methylpropane-2-sulfinamide(530 mg, 1.1 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-3-(morpholin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (450 mg) which was directly used for next step. LC-MS: 365.8[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-3-(morpholin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (450 mg, 1.2 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU(415.7 mg, 1.2 mmol) in dioxan (10 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure. The crude thus obtained was purified by normalsilica column using 20-60% ethyl acetate in hexane to get to get9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(morpholin-4-yl)phenyl) methyl]carbamate (300 mg) as off white solid. LC-MS: 588.0[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(morpholin-4-yl)phenyl) methyl]carbamate (300 mg, 0.5 mmol) in DCM:THF (1:1, 12 mL) wasadded MnO₂ (888 mg, 10.2 mmol) and reaction mass was stirred at 25° C.for 2 h. The reaction mass was filtered through celite pad and thefiltrate was evaporated under reduced pressure. The crude materialobtained was purified by normal silica column using 30-50% ethyl acetatein hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(morpholin-4-yl)phenyl}methyl)carbamate(160 mg) as off white solid with 97% LCMS purity. LC-MS: 585.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 2.79-2.94 (4H, m), 3.66 (4H, s), 4.12-4.23(3H, m), 4.43 (2H, d, J=3.9 Hz), 7.27-7.41 (7H, m), 7.57 (1H, d, J=8.6Hz), 7.63 (2H, d, J=7.3 Hz), 7.88 (2H, d, J=7.1 Hz), 8.30-8.37 (1H, m),8.37-8.44 (1H, m), 10.21 (1H, s).

Intermediate 86 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridazin-4-yl)phenyl}methyl)carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 2.1 mmol) in dioxan (10 mL) were added (pyridazin-4-yl)boronicacid (514 mg, 2.5 mmol), Na₂CO₃ (661 mg, 6.4 mmol), water (5 mL) anddegassed for 10 min in argon atmosphere. Then to it was addedPd(PPh₃)₄(240 mg, 0.21 mmol) and again degassed for 5 min. The reactionmass was heated to 120° C. for 16 h. Reaction mixture was then cooled to25° C., filtered through celite pad, washed with EtOAc. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand concentrated under reduced pressure. The crude thus obtained waspurified by normal silica column using 1-5% methanol in DCM to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridazin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(400 mg) as light yellow solid.

LC-MS: 576.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridazin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(400 mg, 0.7 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyridazin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (250 mg) which was directly used for next step. LC-MS: 358.7[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(pyridazin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (250 mg, 0.7 mmol) in 5% NaHCO₃ (5 mL) was added Fmoc-OSU (235mg, 0.7 mmol) in acetonitrile (5 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridazin-4-yl)phenyl)methyl]carbamate(300 mg, crude) as off white solid. LC-MS: 581.1 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridazin-4-yl)phenyl)methyl]carbamate(300 mg, 0.5 mmol) in DCM/THF (1:1, 10 mL) was added MnO₂ (900 mg, 10.4mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad; filtrate was evaporated under reducedpressure. The crude thus obtained was purified by normal silica columnusing 30-80% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridazin-4-yl)phenyl}methyl)carbamate (130 mg) as a off white solid with 95.2% LCMSpurity. LC-MS: 578.7 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.21 (1H, d, J=7.0 Hz), 4.28 (2H, d, J=6.8Hz), 4.38 (2H, d, J=5.3 Hz), 7.27 (2H, d, J=7.4 Hz), 7.34-7.45 (4H, m),7.67 (2H, d, J=7.1 Hz), 7.87 (4H, d, J=6.5 Hz), 8.03-8.09 (1H, m), 8.16(1H, s), 8.39 (1H, d, J=6.5 Hz), 8.44 (1H, d, J=3.3 Hz), 9.36 (1H, d,J=5.1 Hz), 9.69 (1H, s), 10.21 (1H, s).

Intermediate 87 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-phenylphenyl}methyl)carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 1.9 mmol) in toluene (10 mL) were added phenyl boronic acid (311mg, 2.5 mmol), Na₂CO₃ (625 mg, 5.9 mmol), water (5 mL) and degassed for15 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(114 mg, 0.1mmol) and again degassed for 5 min. The reaction mass was heated to 110°C. for 16 h. Reaction mixture was then cooled to 25° C., filteredthrough celite pad, washed with ethyl acetate. The separated organiclayer was washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-phenylphenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g) as colourless sticky liquid. LC-MS: 575.3 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-phenylphenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 2.1 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-phenylphenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (800 mg) which was directly used for next step. LC-MS: 356.9[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-phenylphenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (800 mg, 2.0 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (685mg, 2.0 mmol) in acetonitrile (40 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-phenylphenyl)methyl]carbamate(1.1 g) as off white solid. LC-MS: 579.3 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-phenylphenyl)methyl]carbamate(1.1 g, 1.9 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (3.3 g, 38mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 0-20% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-phenylphenyl}methyl)carbamate (800 mg) as off white solid with 96% LCMS purity. LC-MS: 577.0[M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.16-4.24 (1H, m), 4.27 (2H, d, J=7.0 Hz),4.36 (2H, d, J=5.6 Hz), 7.25 (2H, t, J=7.5 Hz), 7.36-7.42 (3H, m), 7.49(3H, dt, J=15.5, 7.1 Hz), 7.70 (5H, dd, J=23.8, 7.0 Hz), 7.83-7.89 (3H,m), 7.92 (1H, t, J=6.1 Hz), 8.38 (1H, d, J=6.1 Hz), 8.45 (1H, d, J=4.6Hz), 10.22 (1H, s).

Intermediate 88 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridin-2-yl)phenyl}methyl)carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 3.5 mmol) in toluene (20 mL) were added2-(tributylstannyl)pyridine (1.9 g, 5.2 mmol) and LiCl (44 mg, 1.0 mmol)and degassed in argon atmosphere for 10 min. Then to it was addedPd(PPh3)4 (400 mg, 0.34 mmol) and reaction mass was heated to 110° C.for 16 h. Reaction mixture was then filtered through celite pad andevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 0-60% ethyl acetate in hexane to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridin-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.4 g) as colourless sticky liquid. LC-MS: 576.2 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyridin-2-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.4 g, 2.4 mmol) in MeOH (12 mL), was added 4M HCl in dioxan (6 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyridin-2-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (850 mg) which was directly used for next step. LC-MS: 357.8[M+H]⁺.

To a stirred suspension of((2-{[2-(aminomethyl)-6-chloro-4-(pyridin-2-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (850 mg, 2.2 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (727mg, 2.2 mmol) in acetonitrile (40 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridin-2-yl)phenyl)methyl]carbamate(1.2 g) as off white solid. LC-MS: 580.2 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyridin-2-yl)phenyl)methyl]carbamate(1.2 g, 2.1 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (3.6 g, 41.4mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 10-50% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyridin-2-yl)phenyl}methyl)carbamate(800 mg) as off white solid with 98.0% LCMS purity. LC-MS: 578.1 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.24-4.30 (3H, m), 4.33-4.39 (2H, m), 7.27(2H, t, J=7.4 Hz), 7.35-7.49 (4H, m), 7.69 (2H, d, J=7.1 Hz), 7.88 (2H,d, J=7.1 Hz), 7.96 (2H, dd, J=10.0, 2.1 Hz), 8.05 (1H, d, J=7.1 Hz),8.16 (1H, s), 8.22 (1H, s), 8.34-8.42 (1H, m), 8.44 (1H, d, J=2.7 Hz),8.68 (1H, d, J=3.3 Hz), 10.22 (1H, s).

Intermediate 89 (9H-fluoren-9-yl)methyl5-bromo-3-chloro-2-((2-formylphenyl)thio)benzylcarbamate

To a solution of diisopropylamine (4.02 g, 5.66 ml, 39.7 mmol, Eq: 1.04)in THF (28 ml) was added dropwise (10 min) at −20° C. n-butyllithium,1.6 M in hexane (24.8 ml, 39.7 mmol, Eq: 1.04) and stirred at 0° C. for20 minutes. The mixture was cooled to −78° C. followed by dropwiseaddition (20 minutes) of 4-bromo-2-chloro-1-fluorobenzene (8 g, 38.2mmol, Eq: 1) and the yellow suspension was stirred at −78° C. for 45min. Then was added dropwise (5 minutes—exotherm) N,N-dimethylformamide(4.19 g, 4.44 ml, 57.3 mmol, Eq: 1.5), the cooling bath was removed andthe mixture was allowed to warm to −20° C. to give complete conversion.At −20° C. the clear solution was quenched with sat NH4Cl (80 ml) andextracted with TBME (80 ml). The aqueous layer was extracted again withTBME (40 ml). The organic layers were dried and evaporated. The residue(9.03 g, 100%) was purified by flash chromatography (silica gel) to give5-bromo-3-chloro-2-fluorobenzaldehyde (6.88 g, 76%) as a white solid.

GC-MS: m/z=236.9 (M+H)+ (monoisotopic mass 235.90)

To a solution of 5-bromo-3-chloro-2-fluorobenzaldehyde (1.19 g, 5 mmol,Eq: 1) in DMF (12 ml) was added at 22° C. methyl 2-mercaptobenzoate (867mg, 709 μl, 5 mmol, Eq: 1) followed by potassium carbonate (691 mg, 5mmol, Eq: 1) and stirred at 22° C. for 5 min to give nearly completeconversion. After total 30 minutes the thick suspension was quenchedwith water (25 ml) and extracted with ethyl acetate (2×25 ml). Theorganic layers—containing solid—were combined, the solid was filtered,washed with ethyl acetate (2×6 ml) and dried in HV to give methyl2-((4-bromo-2-chloro-6-formylphenyl)thio)benzoate (1.5 g, 3.89 mmol,77.8% yield) as light yellow solid.

GC-MS: m/z=325.9 (M+H-HCOOMe)+ for monoisotopic mass 383.92 for P1

To a suspension of methyl2-((4-bromo-2-chloro-6-formylphenyl)thio)benzoate (1.43 g, 3.71 mmol,Eq: 1) and 2-methylpropane-2-sulfinamide (449 mg, 3.71 mmol, Eq: 1) inTHF (16 ml) was added at 22° C. Titanium(IV)ethoxide (4.23 g, 3.84 ml,18.5 mmol, Eq: 5) to give a clear yellow solution followed by heating toreflux and stirred at 70° C. for 1 h to give nearly complete conversion.After total 3 h the clear yellow solution was cooled to 22° C. andquenched with sat NaCl (20 ml). The mixture was filtered throughdicalite and washed with ethyl acetate (2×20 ml). The filtrate was driedand evaporated to give (E)-methyl2-((4-bromo-2-(((tert-butylsulfinyl)imino)methyl)-6-chlorophenyl)thio)benzoate(1.73 g, 3.54 mmol, 95.4% yield) (1.73 g, 95%) as light yellow foam.

NMR: mixture of ethyl- and methyl-ester P2/P1 ca. 3:2→yield has to becorrected (ca. 94%)

LC-MS: m/z=488.0 and 490.0 (M+H)⁺ for P1 and second main peak with 502.0and 504.0 (M+H)+ for P2

To a solution of (E)-methyl2-((4-bromo-2-(((tert-butylsulfinyl)imino)methyl)-6-chlorophenyl)thio)benzoate(1.679 g, 3.43 mmol, Eq: 1) in THF (17 ml) was added at 22° C. LiBH4(748 mg, 34.3 mmol, Eq: 10) while color changed immediately to intensivegreen and temperature rised up to 31° C. Mixture was stirred for 10 minto 22° C. to give nearly full reduction of double bond, but still ester.The meanwhile yellow reaction mixture was warmed to 50° C. and stirredat 50° C. for total 20 h: complete conversion. Mixture cooled to 22° C.,quenched dropwise with sat NH4Cl (50 ml) and completely extr. with EtOAc(1×50 ml). The organic layer was washed with sat NaCl (50 ml), dried andevaporated to give 1.53 g (96%) crude product as off-white solid;suspended in 3 ml DCM, solid filtered off, washed with DCM (1×2 ml) andHep/EtOAc-mixture of 4:1 (2×4 ml), dried in HV to give the compoundP-1.1 (811 mg, 51%) as white solid. NMR: OK, but containsborane-signals; LC-MS: m/z=462.0 (M+H)+ For destroying borane-complexP-1.1 was dissolved in THF/EtOAc 2:5 (70 ml) and extracted with 5%KH2PO4 (75 ml—pH 5) and sat NaCl (75 ml); org layer dried and evap togiveN-(5-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzyl)-2-methylpropane-2-sulfinamide(P-1.1=766 mg, 48%) as white solid. NMR: OK; LC-MS: m/z=462.1 (M+H)+ Thepreviously obtained filtrate was purified by flash chrom (silica gel, 40g, EtOAc in heptane 30% to 90%, then MeOH in DCM 9%) to give theadditional product P-1.2 (363 mg, 23%) as white solid. NMR: OK—pure;LC-MS: m/z=462.0 (M+H)+ for monoisotopic mass 460.99 Remarks: totalyield of pure product: P-1.1+P-1.2=1.129 g=71%.

To a suspension ofN-(5-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzyl)-2-methylpropane-2-sulfinamide(330 mg, 713 μmol, Eq: 1) in Methanol (3.3 ml) was added at 0° C. HCl, 4M in dioxane (1.78 ml, 7.13 mmol, Eq: 10), allowed to warm to 22° C.,the solid dissolved completely and it was stirred at 22° C. for 30 minto give complete conversion. The solvent was removed under reducedpressure and dried in HV to give(2-((2-(aminomethyl)-4-bromo-6-chlorophenyl)thio)phenyl)methanolhydrochloride. (334 mg, 119%) off-white solid.

LC-MS: m/z=358.0 (M+H)+ (free amine MW 358.68; 356.96 for monoisotopicmass)

To a solution of(2-((2-(aminomethyl)-4-bromo-6-chlorophenyl)thio)phenyl)methanolhydrochloride (267 mg, 676 μmol, Eq: 1) in Methanol (15 ml) was added at22° C. pyridine (214 mg, 219 μl, 2.7 mmol, Eq: 4) followed by asuspension of (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl)carbonate (239 mg, 709 μmol, Eq: 1.05) in Methanol (3 ml) and stirred at22° C. for 1 h, but still educt was observed. After total 16 h moresolid had precipitated and conversion was nearly complete. The solid wasfiltered off, washed with methanol (2×3 ml) and dried in high vacuum togive (9H-fluoren-9-yl)methyl5-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzylcarbamate (230mg, 59%) as white solid.

LC-MS: m/z=562.0 (M+H-H2O)⁺ for monoisotopic mass 579.03

To a solution of (9H-fluoren-9-yl)methyl5-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzylcarbamate (205mg, 353 μmol, Eq: 1) in THF (7 ml) and DCM (7 ml) (slightly warmed todissolve all solid) was added at 22° C. manganese dioxide (614 mg, 7.06mmol, Eq: 20) and stirred at 22° C. for 3 h to give conversion complete.The mixture was filtered (0.45 RC syringe-filter), washed with THF/DCM1:1 (2×2 ml) and the filtrate was evaporated to give 193 mg crudeproduct. The crude product was suspended in 6 ml DCM/MeOH 1:1, the solidwas filtered off and washed with MeOH (1×2 ml) and DCM (1×2 ml), driedin HV to give the title compound (99 mg, 49%) as white solid.

The filtrate was concentrated (DCM was removed) and the resultingsuspension again filtered. The solid was washed with MeOH (2×2 ml),dried in HV to give the title compound (60 mg, 29%) as white solid.

LC-MS: m/z=560.0 (M+H-H2O)+ for monoisotopic mass 577.01 (weakionisation for molecular mass; main signal for benzyl cation after lossof water) total yield: 159 mg=78% 1H NMR (600 MHz, CDCl₃) δ 10.26 (s,1H), 7.86 (br d, J=7.4 Hz, 1H), 7.76 (br d, J=7.5 Hz, 3H), 7.70 (d,J=2.1 Hz, 1H), 7.65 (s, 1H), 7.52 (br d, J=7.3 Hz, 2H), 7.28-7.45 (m,8H), 6.56 (br d, J=8.0 Hz, 1H), 5.16-5.26 (m, 1H), 4.48 (br d, J=6.3 Hz,2H), 4.38 (br d, J=6.7 Hz, 2H), 4.16 (br t, J=6.9 Hz, 1H).

Intermediate 90 (9H-Fluoren-9-yl)methyl((2,5-dichloro-3-((2-formylphenyl)thio)pyridin-4-yl)methyl)carbamate

This material was prepared in analogy to Intermediate 68 starting from2,3,5-trichloroisonicotinaldehyde and methyl 2-mercaptobenzoate. Thetitle compound was obtained as white solid (2.7 g). ¹H NMR (300 MHz,CHLOROFORM-d) 6=10.27 (s, 1H), 8.52 (s, 1H), 7.94-7.83 (m, 1H), 7.75 (d,J=7.7 Hz, 2H), 7.53-7.28 (m, 8H), 6.56 (br d, J=7.5 Hz, 1H), 5.24 (br s,1H), 4.76 (br d, J=6.0 Hz, 2H), 4.30 (br d, J=6.4 Hz, 2H), 4.10 (br s,1H).

Intermediate 91 (9H-Fluoren-9-yl)methyl((2-chloro-5-((2-formylphenyl)thio)pyridin-4-yl)methyl)carbamate

This material was prepared in analogy to Intermediate 68 starting from2-chloro-5-fluoroisonicotinaldehyde and methyl 2-mercaptobenzoate. Thetitle compound was obtained as white solid (220 mg). MS ESI (m/z): 501.2[(M+H)⁺].

Intermediate 92 (9H-Fluoren-9-yl)methyl3-chloro-2-((3-formylpyridin-4-yl)thio)-5-(trifluoromethyl)benzylcarbamate

To a stirred solution of3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (5 g, 22.07 mmol) inTHF (100 ml) were added 2-methylpropane-2-sulfinamide (2.675 g, 22.07mmol) and Ti(OEt)₄ (23.3 ml, 110.35 mmol) and heated at 70° C. for 2 h.The reaction mixture was quenched with brine solution, ethyl acetate wasadded and filtered. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The crude,thus obtained was purified by silica gel chromatography using ethylacetate in hexane (0-5%) as eluting solvent to affordN-[(1Z)-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide (5.54 g, 76.13%) as yellow liquid. LC-MS:330.1[M+H]⁺.

To a suspension of Na₂S.xH₂O (0.473 g, 6.07 mmol) in DMA (30 ml) wasadded MgSO₄ (4 g) and heated at 105° C. for 1 h. ThenN-[(1Z)-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide (1 g, 3.03 mmol) in DMA (2 ml), MgSO₄ (0.2 g) wasadded to the reaction mixture at the same temperature and continuedheating for another 1 h. Reaction mixture was then cooled to 0° C., Ac₂O(1.2 ml, 6.07 mmol) was added slowly and stirred at 0° C. for another 30min. The reaction mixture was then quenched with water (50 ml) andextracted with ethyl acetate. The combined organic layers were washedwith water, dried over anhydrous sodium sulfate and concentrated undervacuum to afford crude, which was purified (combined with anotherparallel batch) by silica gel chromatography using ethyl acetate inn-hexane (0-6%) as eluting solvent to affordN-[(1Z)-[2-(acetylsulfanyl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide (1.12 g, 48%) as brownliquid. LC-MS: 385.7 [M+H]⁺.

A solution ofN-[(1Z)-[2-(acetylsulfanyl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide (160 mg, 0.42 mmol) in THF (5 ml) was degassedwith argon and then DTT (64 mg, 0.42 mmol) was added. Then reactionmixture was cooled to 0° C., NaBH₄ (156.9 mg, 4.15 mmol) was addedportion wise into the reaction mixture and stirred at the sametemperature for 30 min. The reaction mixture was then quenched withwater (degassed with argon) and extracted with ethyl acetate (degassedwith argon) at 0° C. The organic layer was separated, dried overanhydrous sodium sulfate and concentrated under vacuum (all processesdone under argon atmosphere) to affordN-{[3-chloro-2-sulfanyl-5-(trifluoromethyl)phenyl]methyl}-2-methylpropane-2-sulfinamide (130 mg, crude) as light yellow solid, which wasused as such in the next step. LC-MS: 344.2 [M−H]⁻.

To a stirred solution ofN-{[3-chloro-2-sulfanyl-5-(trifluoromethyl)phenyl]methyl}-2-methylpropane-2-sulfinamide(crude, 100 mg, 0.29 mmol) in dioxane (degassed with argon, 3 ml) wereadded DTT (44.6 mg, 0.29 mmol), 4-chloropyridine-3-carbaldehyde (49.1mg, 0.35 mmol), DIPEA (0.2 ml, 1.16 mmol) and purged with argon. Thenxantphos (16.7 mg, 0.03 mmol), Pd₂(dba)₃ (13.2 mg, 0.01 mmol) were addedto the reaction mixture, again purged with argon and heated at 110° C.for 1.5 h. The reaction mixture was quenched with water (20 ml) andextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The crude,thus obtained was purified by silica gel chromatography using ethylacetate in n-hexane (0-50%) as eluting solvent to affordN-({3-chloro-2-[(3-formylpyridin-4-yl)sulfanyl]-5-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(61 mg, 42%, over 2 steps) as brown solid. LC-MS: 451.02 [M+H]⁺.

To a stirred solution ofN-({3-chloro-2-[(3-formylpyridin-4-yl)sulfanyl]-5-(trifluoromethyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(700 mg, 1.55 mmol) in THF (10 ml) was added NaBH₄ (88.1 mg, 2.33 mmol)portion wise at 0° C. and stirred at 25° C. for 30 min. The reactionmixture was then quenched with aqueous saturated ammonium chloridesolution (15 ml) and extracted with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated undervacuum to affordN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-4-yl]sulfanyl}-5-(trifluoromethyl)phenyl)methyl]-2-methylpropane-2-sulfinamide(685 mg, crude) and was used without further purification. LC-MS: 452.8[M+H]⁺.

To a stirred solution ofN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-4-yl]sulfanyl}-5-(trifluoromethyl)phenyl)methyl]-2-methyl propane-2-sulfinamide (crude, 680 mg, 1.5 mmol)in MeOH (10 ml), was added 4N HCl in dioxan (20 ml) at 0° C. and stirredat 25° C. for 30 min. After completion, reaction mixture wasconcentrated under vacuum to afford(4-{[2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanol hydrochloride (566 mg, crude) asbrown solid and used without further purification. LC-MS: 348.6 [M+H]⁺.

To a stirred suspension of(4-{[2-(aminomethyl)-6-chloro-4-(trifluoromethyl)phenyl]sulfanyl}pyridin-3-yl)methanol hydrochloride (crude, 560 mg, 1.45mmol) in 5% aqueous NaHCO₃ (15 ml) was added Fmoc-OSu (490.3 mg, 1.45mmol) in acetonitrile (25 ml) and stirred at 25° C. for 30 min. Thereaction mixture was diluted with water (25 ml) and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under vacuum. The crude, thus obtained waspurified by silica gel chromatography using ethyl acetate in n-hexane(0-80%) as eluting solvent to afford 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-4-yl]sulfanyl}-5-(trifluoromethyl) phenyl)methyl]carbamate (305mg, 49% over 3 steps). LC-MS: 570.6 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-4-yl]sulfanyl}-5-(trifluoromethyl)phenyl)methyl]carbamate(410 mg, 0.72 mmol) in DCM (10 ml) and THF (10 ml) was added MnO₂ (624.2mg, 7.18 mmol) and stirred at 25° C. for 1 h. After completion ofreaction, reaction mixture was filtered and concentrated under vacuum toafford crude, which was purified by silica gel column chromatographyusing ethyl acetate in n-hexane (0-20%) as eluting solvent to afford9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-4-yl)sulfanyl]-5-(trifluoromethyl)phenyl}methyl) carbamate (151 mg, 37%) as white solid. LC-MS: 569.2[M+H]⁺. 1H NMR: (400 MHz, Chloroform-d) δ 4.11-4.21 (1H, m), 4.40 (2H,d, J=6.8 Hz), 4.48-4.55 (2H, m), 5.24 (1H, ddt, J=6.1, 3.5, 1.0 Hz),6.36-6.44 (1H, m), 7.26-7.34 (2H, m), 7.39 (2H, t, J=6.6 Hz), 7.48-7.56(2H, m), 7.71-7.77 (3H, m), 7.80 (1H, s), 8.35-8.44 (1H, m), 8.94 (1H,s), 10.24 (1H, s).

Intermediate 93 (9H-Fluoren-9-yl)methyl((5-chloro-4-((3-formylpyridin-2-yl)thio)pyridin-3-yl)methyl)carbamate

This material was prepared in analogy to Intermediate 78 starting from4,5-dichloronicotinaldehyde and 2-mercaptonicotinic acid. The titlecompound was obtained as light yellow foam (151 mg). MS ESI (m/z): 502.1[(M+H)⁺].

Intermediate 94 (9H-Fluoren-9-yl)methyl((5-chloro-4-((2-formylphenyl)thio)pyridin-3-yl)methyl)carbamate

This material was prepared in analogy to Intermediate 77 starting from4,5-dichloronicotinaldehyde and methyl 2-mercaptobenzoate. The titlecompound was obtained as light yellow foam (361 mg). MS ESI (m/z): 501.1[(M+H)⁺].

Intermediate 95 (9H-Fluoren-9-yl)methyl((2-chloro-5-((3-formylpyridin-2-yl)thio)pyridin-4-yl)methyl)carbamate

A mixture of 2-mercaptonicotinic acid (2.5 g, 16.1 mmol, Eq: 1) andNa₂CO₃ (5.12 g, 48.3 mmol, Eq: 3) in DMSO (53.7 ml) in a pressure tubewas sparged with argon. Then 2-chloro-5-fluoroisonicotinaldehyde (2.57g, 1.79 ml, 16.1 mmol, Eq: 1) was added, the tube sealed and thereaction mixture stirred at 90° C. for 1.5 h. The mixture was cooled toroom temperature, then dimethyl sulfate (6.1 g, 4.62 ml, 48.3 mmol, Eq:3) was added slowly and the mixture stirred at room temperature for 1 h.Then a solution of 25% aq. ammonia (4.5 g, 5 ml, 66.1 mmol, Eq: 4.1) and5 ml water was added slowly at max. 24° C. and the mixture stirred atroom temperature for 1 h. The reaction mixture was poured into water andextracted with EtOAc. The organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by silica gelchromatography using heptane/ethyl acetate as eluent. Methyl2-((6-chloro-4-formylpyridin-3-yl)thio)nicotinate was obtained as yellowsolid (848 mg). MS ESI (m/z): 309.0 [(M+H)⁺].

Intermediate 96 9H-Fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl) sulfanyl]-5-[2-(morpholin-4-yl)pyridin-4-yl] phenyl} methyl) carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1.5 g, 2.6 mmol) in dioxan (10 mL) were added4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (905mg, 3.12 mmol), Na₂CO₃ (827 mg, 7.8 mmol), water (5 mL) and degassed for10 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(300 mg, 0.26mmol) and again degassed for 5 min. The reaction mass was heated to 120°C. for 16 h. Reaction mixture was then cooled to 25° C., filteredthrough celite pad and washed with EtOAc. The separated organic layerwas washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to get the crude which was purifiedby column chromatography (SiO₂; 100-200 mesh; 50-90% EtOAc/Hexanes) toget N-({2-[(3-{[(tert-butyldimethylsilyl) oxy] methyl} pyridin-2-yl)sulfanyl]-3-chloro-5-[2-(morpholin-4-yl)pyridin-4-yl]phenyl}methyl)-2-methylpropane-2-sulfinamide (1.1 g, 63%)as off white solid. LC-MS: 661.5 [M+H]⁺.

To a stirred solution of N-({2-[(3-{[(tert-butyldimethylsilyl) oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-[2-(morpholin-4-yl)pyridin-4-yl]phenyl}methyl)-2-methylpropane-2-sulfinamide (1.1 g, 1.7mmol) in MeOH (20 mL), was added 4M HCl in dioxan (10 mL) at 0° C. andreaction mixture was stirred at 25° C. for 2 h. Reaction mass wasevaporated under reduced pressure to get (2-{[2-(aminomethyl)-6-chloro-4-[2-(morpholin-4-yl) pyridin-4-yl] phenyl] sulfanyl}pyridin-3-yl) methanol hydrochloride (900 mg) which was directly usedfor next step without further purification. LC-MS: 443.2 [M+H]⁺.

To a stirred suspension of (2-{[2-(aminomethyl)-6-chloro-4-[2-(morpholin-4-yl) pyridin-4-yl] phenyl] sulfanyl}pyridin-3-yl) methanol hydrochloride (900 mg, 1.98 mmol) in 5% NaHCO₃(15 mL) was added Fmoc-OSU (0.667 g, 1.98 mmol) in dioxan (15 mL) at 25°C. and reaction mass was stirred at the same temperature for 16 h. Thenreaction mass was diluted with water and extracted with 10% methanol indichloromethane. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to give 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-[2-(morpholin-4-yl)pyridin-4-yl]phenyl)methyl]carbamate(1.0 g) as sticky solid, which was used for next step without furtherpurification. LC-MS: 665.3 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-[2-(morpholin-4-yl)pyridin-4-yl]phenyl)methyl]carbamatein DCM:THF (1:1, 20 mL) was added MnO₂ (2.62 g, 30.1 mmol) and reactionmass was stirred at 25° C. for 2 h. The reaction mass was filteredthrough celite pad and the filtrate was evaporated under reducedpressure. The crude material obtained was purified by columnchromatography (SiO₂; 100-200 mesh; 40-70% EtOAc/Hexanes) to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-[2-(morpholin-4-yl)pyridin-4-yl]phenyl}methyl)carbamate(290 mg) as off-white solid with 88.5% purity. LC-MS: 663.2 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 3.53 (4H, s), 3.69 (4H, s), 4.21 (1H, d,J=5.9 Hz), 4.26 (2H, d, J=6.4 Hz), 4.36 (2H, d, J=5.1 Hz), 6.99 (1H, d,J=4.5 Hz), 7.13 (1H, s), 7.27 (1H, d, J=7.3 Hz), 7.39 (3H, t, J=7.0 Hz),7.61 (1H, d, J=11.7 Hz), 7.67 (2H, d, J=7.4 Hz), 7.73 (1H, s), 7.88 (3H,d, J=7.5 Hz), 7.99 (1H, s), 8.22 (1H, d, J=5.0 Hz), 8.38 (1H, d, J=7.1Hz), 8.43 (1H, s), 10.22 (1H, s).

Intermediate 97 9H-Fluoren-9-ylmethylN-{[3-chloro-5-(2-chloropyridin-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl] phenyl] methyl} carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2.5 g, 4.3 mmol) in dioxan (20 mL) were added(2-chloropyridin-4-yl)boronic acid (818 mg, 5.2 mmol), Na₂CO₃ (1.4 g, 13mmol), water (10 mL) and degassed for 10 min in argon atmosphere. Tothis was added Pd(PPh₃)₄(501 mg, 0.43 mmol) and again degassed for 5min. The reaction mass was heated to 120° C. for 16 h. Reaction mixturewas cooled to 25° C., filtered through celite pad and washed with EtOAc.The separated organic layer was washed with brine solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude thus obtained was purified by silica column chromatography (SiO₂;100-200 mesh; 50-90% EtOAC/Hexanes) to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-chloropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.8 g) as off white solid. LC-MS: 609.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-chloropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.8 g, 4.6 mmol) in MeOH (30 mL), was added 4M HCl in dioxan (15 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(2-chloropyridin-4-yl) phenyl] sulfanyl}pyridin-3-yl) methanol hydrochloride (1.5 g) as off white sticky solid,which was directly used for next step without further purification.LC-MS: 392.2 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(2-chloropyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.5 g, 3.8 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.3 g, 3.8 mmol) in dioxan (20 mL) at 25° C. and reaction mass wasstirred at the same temperature for 16 h. Then reaction mass was dilutedwith water and extracted with EtOAc. The separated organic layer waswashed with brine, dried over sodium sulfate and evaporated underreduced pressure to get 9H-fluoren-9-ylmethylN-{[3-chloro-5-(2-chloropyridin-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(2.7 g) as off white solid; which was used for next step without furtherpurification. LC-MS: 614.3 [M+H]⁺.

To a stirred solution 9H-fluoren-9-ylmethylN-{[3-chloro-5-(2-chloropyridin-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamatein DCM:THF (1:1, 40 mL) was added MnO₂ (7.66 g, 88.1 mmol) and reactionmass was stirred at 25° C. for 2 h. The reaction mass was filteredthrough celite pad and the filtrate was evaporated under reducedpressure. The crude thus obtained was purified by column chromatography(SiO₂; 100-200 mesh; 40-80% EtOAc/Hexanes) to 9H-fluoren-9-ylmethylN-{[3-chloro-5-(2-chloropyridin-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate(1.5 g) as off-white solid with 96.46% purity. LC-MS: 612.2 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.19-4.37 (5H, m), 7.27 (2H, t, J=7.36 Hz),7.36-7.39 (3H, m), 7.67 (2H, d, J=7.2 Hz), 7.81 (3H, m), 7.88 (2H, d,J=7.21 Hz), 7.94 (1H, m), 8.37 (1H, d, J=7.31 Hz), 8.34 (1H, m), 8.54(1H, d, J=5.12 Hz), 10.21 (1H, s).

Intermediate 98 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(6-hydroxypyridin-3-yl)phenyl}methyl)carbamate

A solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2.5 g, 4.3 mmol), (6-hydroxypyridin-3-yl)boronic acid (0.79 g, 5.6mmol) and sodium carbonate (1.38 g, 13 mmol) in 1,4-dioxane (20 mL) andwater (5 mL) in a sealed tube was degassed with argon for 10 min andPd(PPh₃)₄(0.25 g, 0.22 mmol) was added. The reaction mixture was heatedat 120° C. for 16 h. Progress of the reaction was monitored by TLC.Crude mixture was diluted with water and extracted with EtOAc (100mL×2). Combined organic layer was washed with brine and dried oversodium sulphate, evaporated under reduced pressure to get the crudecompound which was purified by combiflash (70% ethyl acetate in hexane)to affordN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(6-hydroxypyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.0 g) as a brown-orange solid. LC-MS: 592.1 [M+H]⁺.

To an ice-cooled solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(6-hydroxypyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.0 g, 1.69 mmol) in MeOH (20 mL) was added 4M HCl/dioxane (10 mL) andthe reaction mixture was stirred at 25° C. for 2 h. Volatiles wereremoved under reduced pressure to get crude compound which was washedwith diethyl ether (50 mL×2) to get5-(3-chloro-5-ethyl-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)pyridin-2-olhydrochloride (1.0 g, crude) as yellow solid. LC-MS: 373.8 [M+H]⁺.

To a stirred solution of5-(3-chloro-5-ethyl-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)pyridin-2-ol hydrochloride (1.0 g, 2.69 mmol) in CH₃CN (20 mL) was added5% NaHCO₃ solution (20 mL) followed by Fmoc-OSu (0.9 g, 2.69 mmol) inCH₃CN (10 mL) drop-wise and the reaction mixture was stirred at 25° C.for 2 h. Then the reaction mixture was diluted with water (50.0 mL) andextracted with ethyl acetate (3×50 mL). Combined organic layer waswashed with brine solution (3×20 mL), dried over anhydrous sodiumsulphate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(6-hydroxypyridin-3-yl)phenyl)methyl]carbamate(1.0 g) as white solid. LC-MS: 593.8 [M+H]⁺.

To an ice-cooled solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(6-hydroxypyridin-3-yl)phenyl)methyl]carbamate(1.2 g) in DCM (30 mL) was added Dess-Martin periodinane (1.28 g, 3.02mmol) portion-wise. The resulting mixture was then stirred at ambienttemperature for 2 h. Progress of the reaction was monitored by TLC.After completion the reaction mixture was poured onto saturated sodiumbicarbonate solution (100 mL) and organic layer was separated off.Organic layer was washed with sodium thiosulphate solution (2×50 mL),dried over sodium sulphate and concentrated under reduced pressure andthe resulting crude compound was purified by combiflash (70% ethylacetate in hexane) to afford 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(6-hydroxypyridin-3-yl)phenyl}methyl)carbamate(0.25 g) as brown-orange solid with 92% LCMS purity. LC-MS: 594.3[M+H]⁺.

1H NMR (400 MHz, DMSO-d6) δ 4.21 (1H, d, J=6.1 Hz), 4.26 (2H, d, J=6.7Hz), 4.32 (2H, d, J=5.8 Hz), 6.45 (1H, d, J=9.5 Hz), 7.28 (2H, t, J=7.4Hz), 7.34-7.44 (3H, m), 7.57 (1H, d, J=1.5 Hz), 7.67 (2H, d, J=7.5 Hz),7.78-7.92 (7H, m), 8.36 (1H, dd, J=7.6, 1.7 Hz), 8.43 (1H, dd, J=4.7,1.7 Hz), 10.20 (1H, s), 12.04 (1H, s).

Intermediate 99 9H-fluoren-9-ylmethylN-({3-chloro-5-[6-(dimethylamino)pyridin-3-yl]-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate

A solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2.5 g, 4.33 mmol), [6-(dimethylamino) pyridine-3-yl]boronic acid (0.93g, 5.63 mmol) and sodium carbonate (1.38 g, 13 mmol) in 1,4-dioxane (20mL) and water (5 mL) was degassed with argon for 10 min and Pd(PPh₃)₄(0.25 g, 0.22 mmol) was added. Then the reaction mixture washeated at 120° C. for 2 h. Progress of the reaction was monitored byTLC. Crude reaction mixture was diluted with water and extracted withEtOAc (100 mL×2). Combined organic layer was washed with brine and driedover sodium sulphate and concentrated under reduced pressure. Crudecompound was purified by combiflash (80% ethyl acetate in hexane) toaffordN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-[6-(dimethylamino)pyridin-3-yl]phenyl}methyl)-2-methylpropane-2-sulfinamide(0.85 g) as an off-white solid. LC-MS: 618.8 [M+H]⁺.

To an ice-cooled solution of N-({2-[(3-{[(tert-butyldimethylsilyl) oxy]methyl} pyridin-2-yl) sulfanyl]-3-chloro-5-[6-(dimethylamino)pyridin-3-yl] phenyl} methyl)-2-methylpropane-2-sulfinamide (0.85 g, 1.4mmol) in MeOH (20 mL) was added 4M HCl in dioxane (8.0 mL) and thereaction mixture was stirred at 25° C. for 2 h. Volatiles were removedunder reduced pressure to get crude compound which was washed withdiethyl ether (50 mL×2) to get[2-({2-chloro-4-[6-(dimethylamino)pyridin-3-yl]-6-ethylphenyl}sulfanyl)pyridin-3-yl]methanolhydrochloride (1.0 g) as yellow solid. LC-MS: 400.8 [M+H]⁺.

To a stirred suspension of[2-({2-chloro-4-[6-(dimethylamino)pyridin-3-yl]-6-ethylphenyl}sulfanyl)pyridin-3-yl]methanol hydrochloride (1.0 g, crude, 2.5 mmol) in CH₃CN(20.0 mL) was added 5% NaHCO₃ (20 mL) followed by Fmoc-OSu (0.84 g, 2.5mmol) in CH₃CN (30 mL) and the reaction mixture was stirred at 25° C.for 2 h. After completion, the reaction mixture was diluted with water(50 mL) and was extracted with ethyl acetate (3×50 mL). Combined organiclayer was washed with brine solution (3×20 mL), dried over anhydroussodium sulphate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-({3-chloro-5-[6-(dimethylamino)pyridin-3-yl]-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl}methyl)carbamate(1.1 g) as white solid. LC-MS: 623.3 [M+H]⁺. To an ice-cooled solutionof 9H-fluoren-9-ylmethylN-({3-chloro-5-[6-(dimethylamino)pyridin-3-yl]-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl}methyl)carbamate(1.1 g) in DCM (30 mL) was added Dess-Martin periodinane (1.12 g, 2.65mmol) portion-wise and the reaction mixture was then stirred at 25° C.for 2 h. Then the reaction mixture was poured onto saturated sodiumbicarbonate solution (2×50 mL) and organic layer was separated off.Organic layer was washed with sodium thiosulphate solution (2×50 mL),dried over sodium sulphate and concentrated under reduced pressure togive crude compound which was purified by combiflash (2% MeOH in DCM) toafford 9H-fluoren-9-ylmethylN-({3-chloro-5-[6-(dimethylamino)pyridin-3-yl]-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate(0.35 g) as brown-orange solid with 91% LCMS purity.

LC-MS: 621.2 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6) δ 3.10 (6H, s), 4.22 (1H, d, J=6.1 Hz), 4.27(2H, d, J=6.6 Hz), 4.33 (2H, d, J=5.9 Hz), 7.29 (2H, t, J=7.5 Hz),7.33-7.46 (4H, m), 7.62 (1H, s), 7.69 (2H, d, J=7.5 Hz), 7.81 (1H, d,J=1.6 Hz), 7.88 (4H, d, J=8.1 Hz), 8.37 (1H, dd, J=7.6, 1.6 Hz), 8.45(1H, dd, J=4.6, 1.6 Hz), 8.52 (1H, d, J=2.2 Hz), 10.21 (1H, s).

Intermediate 100 9H-fluoren-9-ylmethylN-[[4-bromo-3-chloro-2-(2-formylphenyl)sulfanyl-phenyl]methyl]carbamate

To a mechanical-stirred solution of diisopropylamine (5.02 g, 7.08 ml,49.7 mmol, Eq: 1.04) in THF (35 ml) was added dropwise (5 min) at −20°C. n-butyllithium, 1.6 M in hexane (31 ml, 49.7 mmol, Eq: 1.04) andstirred at 0° C. for 20 minutes. The mixture was cooled to −78° C.followed by dropwise addition (20 minutes) of a solution of1-bromo-2-chloro-3-fluorobenzene (10 g, 47.7 mmol, Eq: 1) in THF (10 ml)and the thick yellow suspension was stirred at −78° C. for 60 min. Thenwas added dropwise (5 minutes—exotherm) N,N-dimethylformamide (5.23 g,5.55 ml, 71.6 mmol, Eq: 1.5), the cooling bath was removed and themixture was allowed to warm to −20° C. to give complete conversion. At−20° C. the clear yellow solution was quenched with sat NH4Cl (100 ml)and extracted with TBME (100 ml). The aqueous layer was extracted againwith TBME (50 ml). The organic layers were dried and evaporated at only50 mbar for short time. The yellow residue was dissolved inheptane/ethyl acetate 10:1 (ca. 30 ml) at 55° C., concentrated to ⅓ andstirred to 22° C. while crystallisation started. After 30 minutes thesuspension was cooled to 0° C. for 30 minutes, the solid was filteredoff, washed with heptane (2×15 ml) and dried (only short time) to give4-bromo-3-chloro-2-fluorobenzaldehyde (5.27 g, 47%) as light yellowsolid.

The filtrate was evaporated and purified by flash chromatography (silicagel, 70 g, adsorbed on isolute sorbent HM-N, EtOAc in heptane, 0% to 5%)to give additional compound (4.073 g, 36%) as off-white solid.

GC-MS: m/z=235.9 M.+(monoisotopic mass 235.90)

To a solution of 4-bromo-3-chloro-2-fluorobenzaldehyde (4.073 g, 17.2mmol, Eq: 1) in DMF (41 ml) was added at 22° C. potassium carbonate(2.37 g, 17.2 mmol, Eq: 1) followed by methyl 2-mercaptobenzoate (2.98g, 2.43 ml, 17.2 mmol, Eq: 1) (internal temperature rised up to 24° C.cooling with waterbath) and stirred for 1 h to give complete conversion.The yellow emulsion was quenched with water (100 ml—exotherm) andextracted with ethyl acetate (100 ml), but no phase separation. Additionof 5 g sodium chloride to give separation of layers. The aqueous layerwas extracted with ethyl acetate (1×50 ml). The organic layers werewashed with sat NaCl (1×50 ml), dried and evaporated. The residue waspurified by flash chromatography (silica gel, 330 g, adsorbed on 10 gIsolute HM-N, EtOAc in heptane 0% to 10% to 20% to 40%) to give methyl2-((3-bromo-2-chloro-6-formylphenyl)thio) benzoate (2.546 g, 39%) as alight yellow solid.

LC-MS: m/z=385.0 (M+H)+ (monoisotopic mass 383.92)

To a turbid solution of methyl2-((3-bromo-2-chloro-6-formylphenyl)thio)benzoate (2.48 g, 6.43 mmol,Eq: 1) and 2-methylpropane-2-sulfinamide (779 mg, 6.43 mmol, Eq: 1) inTHF (28 ml) was added at 22° C. Titanium(IV)ethoxide (7.33 g, 6.67 ml,32.2 mmol, Eq: 5) to give a clear yellow solution followed by heating toreflux and stirred at 70° C. for 30 min to give complete conversion. Thelight turbid yellow solution was cooled to 22° C. and quenched with satNaCl (30 ml) to give a thick suspension. The mixture was filteredthrough dicalite and washed with ethyl acetate (2×30 ml). The filtrate(1-phase-system) was dried and evaporated to give a mixture of(E)-methyl2-((3-bromo-6-(((tert-butylsulfinyl)imino)methyl)-2-chlorophenyl)thio)benzoateand (E)-ethyl2-((3-bromo-6-(((tert-butylsulfinyl)imino)methyl)-2-chlorophenyl)thio)benzoate(3.04 g, 6.22 mmol, 97% yield) as yellow solid.

NMR: mixture of methyl- and ethyl-ester, ratio ca. 3:1

LC-MS: m/z=488.0 (M+H)+ for methyl ester (MW 486.97 for monoisotopicmass) and 502.0 (M+H)+ for ethyl ester

To a solution of (E)-methyl2-((3-bromo-6-(((tert-butylsulfinyl)imino)methyl)-2-chlorophenyl)thio)benzoate(3.04 g, 6.22 mmol, Eq: 1,3:1 mixture of methyl and ethyl esters) in THF(60 ml) was added at 22° C. lithium borohydride (1.35 g, 62.2 mmol, Eq:10) in one portion under waterbath cooling while color changedimmediately to intensive green and internal temperature rised up to 31°C. After decolorisation (5 minutes) the mixture was warmed to 50° C. andstirred at 50° C. for 24 h to give complete conversion. The mixture wascooled to 22° C., quenched dropwise (effervescensing andexothermic—cooling with ice-water bath) with sat NH4Cl (50 ml) andcompletely extracted with ethyl acetate (1×50 ml). The organic layer waswashed with 5% KH2PO4 (1×50 ml, pH 5 to destroy borane-complex) and satNaCl (1×50 ml), dried and evaporated to give crude product as whitesolid. The solid was dissolved in 50 ml ethyl acetate under reflux,cooled to 22° C. while 50 ml heptane was added in one portion. Thesolution was stirred for 30 minutes at 22° C. while crystallisationstarted. Then cooled to 5° C. and stirred for 30 minutes, the solid wasfiltered off, washed with EtOAc/Hep 1:1 (1×20 ml) and pentane (1×20 ml)and dried in HV to giveN-(4-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzyl)-2-methylpropane-2-sulfinamide(2.296 g, 80%) as white solid.

LC-MS: m/z=484.0 (M+Na)+ (monoisotopic mass 460.99)

To a suspension ofN-(4-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzyl)-2-methylpropane-2-sulfinamide(1.5 g, 3.24 mmol, Eq: 1) in Methanol (15 ml) was added at 0° C. HCl, 4M in dioxane (8.1 ml, 32.4 mmol, Eq: 10), allowed to warm to 22° C.while solid dissolved completely and stirred at 22° C. for 60 min togive complete conversion. The solvent was removed under reduced pressureand dried in HV to(2-((6-(aminomethyl)-3-bromo-2-chlorophenyl)thio)phenyl)methanolhydrochloride (1.56 g, 122%) as off-white foam.

NMR: contains tert-butylsulfinic acid, no further purification—used asis in next step

LC-MS: m/z=358.0 (M+H)+ (monoisotopic mass 356.96)

To a solution of(2-((6-(aminomethyl)-3-bromo-2-chlorophenyl)thio)phenyl)methanolhydrochloride (1.51 g, 3.82 mmol, Eq: 1) in Methanol (90 ml) was addedat 22° C. pyridine (1.21 g, 1.24 ml, 15.3 mmol, Eq: 4) followed by(9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.35 g,4.01 mmol, Eq: 1.05) and stirred at 22° C. for 20 h while more solid hadprecipitated to give conversion complete. The solid was filtered off,washed with methanol/pentane 1:2 (1×30 ml), pentane (1×30 ml) and driedin HV to give (9H-fluoren-9-yl)methyl4-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio) benzylcarbamate(1.174 g, 53%) as white solid.

LC-MS: m/z=602.0 (M+Na)+(monoisotopic mass 579.03)

To a solution of (9H-fluoren-9-yl)methyl4-bromo-3-chloro-2-((2-(hydroxymethyl)phenyl)thio)benzylcarbamate (1.115g, 1.92 mmol, Eq: 1) in THF (38 ml) and DCM (38 ml) was added at 22° C.manganese dioxide (3.34 g, 38.4 mmol, Eq: 20) and stirred at 22° C. for3 h to give conversion complete. The mixture was filtered(membrane-filter), washed with THF/DCM 1:1 (2×10 ml) and the filtratewas evaporated to give crude product as yellow foam The residue wasdissolved nearly completely in 15 ml DCM, but then startingcrystallisation in syringe (planned to inject onto column). The solidwas filtered off, washed with DCM (2×5 ml) and dried to give 208 mg(=19%, P1) white solid. The filtrate was purified by flashchromatography (silica gel, 40 g, EtOAc in heptane 0% to 100% then MeOHin DCM 10%), the product fractions were combined with P1 and allevaporated and dried in HV to give (9H-fluoren-9-yl)methyl4-bromo-3-chloro-2-((2-formylphenyl)thio)benzylcarbamate (0.95 g, 86%)as white solid.

LC-MS: m/z=560.1 (M+H-H2O)+ (monoisotopic mass 577.01)

1H NMR (600 MHz, CDCl₃) δ 10.26 (s, 1H), 7.86 (br d, J=7.1 Hz, 1H),7.73-7.78 (m, 3H), 7.51 (br d, J=7.5 Hz, 2H), 7.40 (t, J=7.4 Hz, 3H),7.28-7.33 (m, 1H), 7.27-7.31 (m, 2H), 7.27-7.36 (m, 2H), 6.55 (br dJ,=7.7 Hz, 1H), 5.22 (br t, J=5.9 Hz, 1H), 4.45 (br d, J=6.3 Hz, 2H), 4.38(d, J=6.7 Hz, 2H), 4.15 (t, J=6.5 Hz, 2H).

Intermediate 101 9H-fluoren-9-ylmethyN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(4-methanesulfonylphenyl)phenyl}methyl)carbamate

A solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2.5 g, 4.33 mmol), (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (0.79 g,5.63 mmol) and sodium carbonate (1.38 g, 13 mmol) in 1,4-dioxane (20 mL)and water (5 mL) was degassed with argon for 10 min and Pd(PPh₃)₄(0.25g, 0.22 mmol) was added. Then the reaction mixture was heated at 120° C.for 16 h. Progress of the reaction was monitored by TLC. Crude reactionmixture was diluted with water, extracted with EtOAc (25 mL×2), washedwith brine and dried over sodium sulphate. Organic layer wasconcentrated under reduced pressure and the crude compound thus obtainedwas purified by combiflash (70% ethyl acetate in hexane) to affordN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2 g) as a brown-orange solid. LC-MS: 594.2 [M+H]⁺.

To an ice-cooled solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.0 g, 3.4 mmol) in MeOH (20 mL) was added 4M HCl in dioxane (15 mL)and the reaction mixture was stirred at 25° C. for 2 h. Then thevolatiles were removed under reduced pressure to get crude compoundwhich was then washed with diethyl ether (50 mL×2) to get(2-{[2-(aminomethyl)-6-chloro-4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.0 g, crude) as yellow solid. LC-MS: 376.1 [M+H]⁺.

To a stirred solution of(2-{[2-(aminomethyl)-6-chloro-4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.0 g, crude) in CH₃CN (20 mL) was added 5% NaHCO₃solution (20 mL) followed by Fmoc-OSu (0.9 g, 2.67 mmol) in CH₃CN (10.0mL) drop-wise and the reaction mixture was stirred at 25° C. for 2 h.Then the reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (3×50 mL). Combined organic layer was washed withbrine solution (3×20 mL), dried over anhydrous sodium sulphate andevaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-{[3-chloro-5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(1.4 g) as brown solid. LC-MS: 597.8 [M+H]⁺.

To an ice-cooled solution of 9H-fluoren-9-ylmethylN-{[3-chloro-5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(1.4 g) in DCM (30.0 mL) was added Dess-Martin periodinane (1.49 g, 3.51mmol) portion-wise and the reaction mixture was stirred at 25° C. for 2h. Progress of the reaction was monitored by TLC. After completion thereaction mixture was poured in saturated sodium bicarbonate solution(100 mL) and organic layer was separated off. Organic layer was washedwith sodium thiosulphate solution (2×50 mL), dried over sodium sulphateand concentrated under reduced pressure and the resulting crude compoundwas purified by combiflash (1% methanol in DCM) to afford9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(4-methanesulfonylphenyl)phenyl}methyl)carbamate(0.3 g) as a brown-orange solid with 96% LCMS purity. LC-MS: 596.3[M+H]⁺.

1H NMR (400 MHz, DMSO-d6) δ 2.25 (3H, s), 2.41 (3H, s), 4.20 (1H, t,J=6.8 Hz), 4.29 (4H, d, J=6.4 Hz), 7.26 (3H, d, J=8.5 Hz), 7.36-7.40(3H, m), 7.62 (1H, s), 7.66 (2H, d, J=7.5 Hz), 7.87-7.91 (3H, m), 8.38(1H, d, J=7.7 Hz), 8.47 (1H, dd, J=4.8, 1.6 Hz), 10.21 (1H, s).

Intermediate 102 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(4-methanesulfonylphenyl)phenyl}methyl)carbamate

To a stirred solution ofN-[(5-bromo-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide (10 g, 21.56 mmol) in DCM (100 mL)were added imidazole (4.4 g, 64.68 mmol) and TBDMSCl (4.87 g, 32.34mmol) sequentially and the reaction mixture was stirred at 25° C. for 2h. After completion, the reaction mixture was washed with sodiumbicarbonate solution and extracted with DCM (100 mL×3). Combined organiclayer was concentrated under reduced pressure to get the crude compoundwhich was purified by combiflash (60% ethyl acetate in hexane) to getN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(10 g) as an off-white solid. LC-MS: 579.2 [M+2H]⁺.

A solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2.6 g, 4.51 mmol), (4-methanesulphonyl phenyl)boronic acid (1.17 g,5.86 mmol) and sodium carbonate (1.43 g, 13.52 mmol) in 1,4-dioxane (20mL) and water (5.0 mL) was degassed with argon for 10 min andPd(PPh₃)₄(0.26 g, 0.23 mmol) was added. Then the reaction mixture washeated at 120° C. for 4 h. Progress of the reaction was monitored byTLC. Crude mixture was diluted with water, extracted with EtOAc (50mL×2), washed with brine and dried over sodium sulphate and concentratedunder reduced pressure. The crude compound thus obtained was purified bycolumn chormatography (70% ethyl acetate in hexane) to affordN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4-methanesulfonylphenyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2. g, 68%) as yellow solid. LC-MS: 653.4[M+H]⁺.

To an ice cooled solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4-methanesulfonylphenyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.0 g, 3.1 mmol) in MeOH (20 mL) was added 4M HCl in dioxane (15 mL)and the reaction mixture was at 25° C. for 2 h. Then volatiles wereremoved under reduced pressure to get crude compound which was washedwith diethyl ether (50 mL×2) to get(2-{[2-(aminomethyl)-6-chloro-4-(4-methanesulfonylphenyl)phenyl]sulfanyl}pyridin-3-yl)methanol hydrochloride (1.2g) as yellow solid. LC-MS: 435.0 [M+H]⁺.

To a stirred solution of(2-{[2-(aminomethyl)-6-chloro-4-(4-methanesulfonylphenyl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.2 g, 2.76 mmol) in CH₃CN (20 mL) was added 5% NaHCO₃solution (20 mL) followed by Fmoc-OSu (0.93 g, 2.77 mmol) in CH₃CN (10.0mL) drop-wise and the reaction mixture was stirred at 25° C. for 2 h.Then the reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (3×50 mL). Combined organic layer was washed withbrine (3×20 mL), dried over anhydrous sodium sulphate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(4-methanesulfonylphenyl)phenyl)methyl]carbamate(1.2 g) as yellow solid. LC-MS: 656.6 [M+H]⁺.

To an ice-cooled solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(4-methanesulfonylphenyl)phenyl)methyl]carbamate(0.9 g, crude) in DCM (30 mL) was added Dess-Martin periodinane (0.87 g,2.05 mmol) portion-wise and the reaction mixture was then stirred at 25°C. for 2 h. Then the reaction mixture was poured onto saturated sodiumbicarbonate solution (100 mL) and organic layer was separated off.Organic layer was washed with sodium thiosulphate solution (50×2 mL),dried over sodium sulphate and concentrated under reduced pressure andthe resulting crude compound was purified by combiflash (1% methanol inDCM) to afford 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(4-methanesulfonylphenyl)phenyl}methyl)carbamate(0.3 g, 15% over 3 steps) as brown-orange solid with 96% LCMS purity.LC-MS: 655.3 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6) δ 3.29 (3H, s), 4.21 (1H, d, J=6.7 Hz), 4.27(2H, d, J=7.0 Hz), 4.37 (2H, d, J=6.1 Hz), 7.24 (2H, t, J=7.4 Hz), 7.37(2H, d, J=7.4 Hz), 7.38-7.45 (1H, m), 7.67 (2H, d, J=7.4 Hz), 7.73 (1H,s), 7.87 (2H, d, J=7.5 Hz), 7.93 (1H, t, J=5.6 Hz), 7.96-8.00 (2H, m),8.04 (3H, t, J=9.6 Hz), 8.39 (1H, dd, J=7.6, 1.6 Hz), 8.46 (1H, dd,J=4.7, 1.6 Hz), 10.22 (1H, s).

Intermediate 103 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(5-methanesulfonylpyridin-3-yl)phenyl}methyl)carbamate

A solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide (0.6 g, 1.04 mmol),(5-methanesulfonylpyridin-3-yl)boronic acid (0.27 g, 1.35 mmol) andsodium carbonate (0.33 g, 3.12 mmol) in 1,4-dioxane (25 mL) and water (5mL) in a sealed tube was degassed with argon for 10 min andPd(PPh₃)₄(0.06 g, 0.05 mmol) was added. The reaction mixture was heatedat 120° C. for 4 h. Progress of the reaction was monitored by TLC. Crudemixture was diluted with water and extracted with EtOAc (50 mL×2).Combined organic layers were washed with brine, dried over sodiumsulphate, evaporated under reduced pressure and the crude compound waspurified by column chromatography (70% ethyl acetate in hexane) toafford N-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(5-methanesulfonylpyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(0.42 g, 62%) as yellow solid. LC-MS: 653.6 [M+H]⁺.

To an ice-cooled solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(5-methanesulfonylpyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.2 g, 1.83 mmol) in MeOH (20 mL) was added 4M HCl in dioxane (12 mL)and the reaction mixture was stirred at 25° C. for 2 h. Volatiles wereremoved under reduced pressure to give crude compound which was washedwith diethyl ether (50 mL×2) and dried to get(2-{[2-(aminomethyl)-6-chloro-4-(5-methanesulfonylpyridin-3-yl)phenyl]sulfanyl}pyridin-3-yl)methanol(1 g, crude) as white solid. LC-MS: 436.1 [M+H]⁺.

To a stirred solution of{2-[2-aminomethyl-6-chloro-4-(5-methanesulfonyl-pyridin-3-yl)-phenylsulfanyl]-pyridin-3-yl}-methanol hydrochloride (1 g, 2.3 mmol) in CH₃CN(20 mL) was added 5% NaHCO₃ solution (20 mL) followed by Fmoc-OSu (0.78g, 2.3 mmol) in CH₃CN (10 mL) drop-wise and the reaction mixture wasstirred at 25° C. for 2 h. Then the reaction mixture was diluted withwater (50 mL) and extracted with ethyl acetate (3×50 mL). Combinedorganic layer was washed with brine solution (3×20 mL), dried overanhydrous sodium sulphate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(5-methanesulfonylpyridin-3-yl)phenyl)methyl]carbamate(1.1 g, crude) as white solid. LC-MS: 658.4 [M+H]⁺.

To an ice-cooled solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(5-methanesulfonylpyridin-3-yl)phenyl)methyl]carbamate(1.1 g, crude) in DCM (30 mL) was added Dess-Martin periodinane (1.06 g,2.51 mmol) portion-wise and the reaction mixture was then stirred at 25°C. for 2 h. Then the reaction mixture was poured onto saturated sodiumbicarbonate solution (2×50 mL) and organic layer was separated off.Organic layer was washed with sodium thiosulphate solution (2×50 mL),dried over sodium sulphate and concentrated under reduced pressure andthe resulting crude compound was purified by column chromatography (50%ethyl acetate in hexane) to afford 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(5-methanesulfonylpyridin-3-yl)phenyl}methyl)carbamate(0.55 g) as brown-orange solid with 91% LCMS purity. LC-MS: 656.3[M+H]⁺.

1H NMR (400 MHz, DMSO-d6) δ 3.42 (3H, s), 4.20 (1H, d, J=6.7 Hz), 4.27(2H, d, J=6.9 Hz), 4.38 (2H, d, J=5.6 Hz), 7.25 (2H, t, J=7.4 Hz), 7.37(3H, t, J=7.5 Hz), 7.65 (2H, d, J=7.5 Hz), 7.82-7.92 (4H, m), 8.13 (1H,s), 8.39 (1H, d, J=7.5 Hz), 8.43 (1H, d, J=4.7 Hz), 8.66 (1H, s), 9.14(1H, s), 9.30 (1H, s), 10.22 (1H, s).

Intermediate 1044-[3-Chloro-5-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-4-(3-formyl-pyridin-2-ylsulfanyl)-phenyl]-3,5-dimethyl-pyrazole-1-carboxylicacid 9H-fluoren-9-ylmethyl ester

A solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide (2.5 g, 4.33 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.25 g, 5.63 mmol) and sodium carbonate (1.38 g, 12.99 mmol) in1,4-dioxane (20 mL) and water (5.0 mL) was degassed with argon for 10min and Pd(PPh₃)₄(0.25 g, 0.22 mmol) was added. Then the reactionmixture was heated at 120° C. for 16 h. Progress of the reaction wasmonitored by TLC. Then the crude reaction mixture was diluted with waterand extracted with EtOAc (50 mL×2), washed with brine, dried over sodiumsulphate and evaporated under reduced pressure. The crude compound thusobtained was purified by column chromatography (90% ethyl acetate inhexane) to afford N-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (0.9 g) as brown solid. LC-MS: 593.1 [M+H]⁺.

To an ice-cooled solution of N-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(0.9 g, 1.517 mmol) in MeOH (20 mL) was added 4M HCl in dioxane (10.0mL) and the reaction mixture was stirred at 25° C. for 2 h. Thenvolatiles were removed under reduced pressure to give pale orangecolored crude solid compound which was then washed with diethyl ether(50 mL×2) to get(2-{[2-(aminomethyl)-6-chloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (0.9 g, crude) as yellow solid. LC-MS: 374.8 [M+H]⁺.

To a stirred solution of(2-{[2-(aminomethyl)-6-chloro-4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.1 g, 2.94 mmol) in CH₃CN (20 mL) was added 5% NaHCO₃solution (10 mL) followed by Fmoc-OSu (1.98 g, 5.88 mmol) in CH₃CN (10.0mL) drop-wise and the reaction mixture was stirred at 25° C. for 2 h.Then the reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (3×50 mL). Combined organic layer was washed withbrine (3×20 mL), dried over anhydrous sodium sulphate and concentratedunder reduced pressure. The crude compound thus obtained was purified bycombiflash (2-5% methanol in DCM) to get 9H-fluoren-9-ylmethylN-{[3-chloro-5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(0.4 g) as a white solid and 9H-fluoren-9-ylmethyl4-[3-chloro-5-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]-3,5-dimethyl-1H-pyrazole-1-carboxylate(0.6 g) as an off-white solid. LC-MS: 819.7 [M+H]⁺.

To an ice-cooled solution of 9H-fluoren-9-ylmethyl4-[3-chloro-5-({[(9H-fluorene-9-ylmethoxy)carbonyl]amino}methyl)-4-{[3-(hydroxymethyl)pyridine-2-yl]sulfanyl}phenyl]-3,5-dimethyl-1H-pyrazol-1-carboxylate(0.5 g, 0.61 mmol) in DCM (20.0 mL) was added Dess-Martin periodinane(0.39 g, 0.92 mmol) portion-wise and the reaction mixture was stirred at25° C. for 2 h. Then the reaction mixture was poured onto saturatedsodium bicarbonate solution (100 mL) and organic layer was separatedoff. Organic layer was washed with sodium thiosulphate solution (2×50mL), dried over sodium sulphate and concentrated under reduced pressureand the resulting crude compound was purified by combiflash (1% methanolin DCM) to afford 9H-fluoren-9-ylmethyl4-[3-chloro-5-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-4-[(3-formylpyridin-2-yl)sulfanyl]phenyl]-3,5-dimethyl-1H-pyrazole-1-carboxylate(0.27 g, 54%) as brown-orange solid with 91% LCMS purity. LC-MS: 817.4[M+H]⁺.

1H NMR (400 MHz, DMSO-d6) δ 2.03 (3H, s), 2.21 (3H, s), 4.29 (5H, d,J=5.9 Hz), 4.48 (1H, t, J=5.6 Hz), 4.84 (2H, d, J=6.0 Hz), 7.15-7.22(6H, m), 7.28-7.36 (6H, m), 7.41 (4H, t, J=7.5 Hz), 7.50 (1H, s), 7.65(2H, d, J=7.4 Hz), 7.80 (2H, d, J=7.5 Hz), 7.88 (5H, t, J=6.6 Hz), 8.38(1H, d, J=7.3 Hz), 8.47 (1H, d, J=3.6 Hz), 10.21 (1H, s).

Intermediate 105 9H-Fluoren-9-ylmethylN-{[3-chloro-5-(2-fluoropyridin-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl] phenyl] methyl} carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(10.0 g, 17.3 mmol) in dioxan (50 mL) were added(2-fluoropyridin-4-yl)boronic acid (2.93 g, 20.8 mmol), Na₂CO₃ (5.51 g,52 mmol), water (25 mL) and degassed for 10 min in argon atmosphere.Then to it was added Pd(PPh₃)₄(2.0 g, 1.73 mmol) and again degassed for5 min. The reaction mass was heated to 120° C. for 16 h. Reactionmixture was then cooled to 25° C., filtered through celite pad andwashed with EtOAc. The separated organic layer was washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to get the crude which was purified by column chromatography(SiO₂; 100-200 mesh; 50-90% EtOAc/Hexanes) to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-fluoropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(7.5 g, 72%) as off white solid. LC-MS: 593.9 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(2-fluoropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(7.5 g, 12.6 mmol) in MeOH (50 mL), was added 4M HCl in dioxan (25 mL)at 0° C. and reaction mixture was stirred at 25° C. for 2 h. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(2-fluoropyridin-4-yl) phenyl] sulfanyl}pyridin-3-yl)methanol hydrochloride (6.5 g, crude) which was directlyused for next step without further purification.

LC-MS: 376.0 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(2-fluoropyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (6.5 g, 17.33 mmol) in 5% NaHCO₃ (50 mL) was addedFmoc-OSU (5.84 g, 17.33 mmol) in dioxan (50 mL) at 25° C. and reactionmass was stirred at the same temperature for 16 h. Then reaction masswas diluted with water and extracted with 10% methanol indichloromethane. The separated organic layer was washed with brinesolution, dried over sodium sulfate and evaporated under reducedpressure to 9H-fluoren-9-ylmethylN-{[3-chloro-5-(2-fluoropyridin-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(8.0 g) as off-white solid; which was used for next step without furtherpurification. LC-MS: 598.1 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[3-chloro-5-(2-fluoropyridin-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamatein DCM/THF (1:1, 100 mL) was added MnO₂ (23.3 g, 268.0 mmol) andreaction mass was stirred at 25° C. for 2 h. The reaction mass wasfiltered through celite pad; filtrate was evaporated under reducedpressure. The crude thus obtained was purified by column chromatography(SiO₂; 100-200 mesh; 40-80% EtOAc/Hexanes) to get 9H-fluoren-9-ylmethylN-{[3-chloro-5-(2-fluoropyridin-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate(5.2 g) as off-white solid with 95.7% purity. LC-MS: 596.1 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.20 (1H, t, J=7.1 Hz), 4.28 (2H, d, J=6.9Hz), 4.38 (2H, d, J=5.5 Hz), 7.26 (2H, t, J=7.4 Hz), 7.36-7.40 (3H, m),7.62 (1H, s), 7.67 (2H, d, J=7.5 Hz), 7.74 (1H, d, J=5.0 Hz), 7.82 (1H,s), 7.87 (3H, d, J=7.5 Hz), 8.08 (1H, s), 10.21 (1H, s).

Intermediate 106 RO7189105-000 (9H-Fluoren-9-yl)methyl((5-chloro-2-((2-formylphenyl)thio)pyridin-3-yl)methyl)carbamate

This material was prepared in analogy to Intermediate 68 starting from2,5-dichloronicotinaldehyde and methyl 2-mercaptobenzoate. The titlecompound was obtained as light yellow foam (230 mg). MS ESI (m/z): 501.1[(M+H)⁺].

Intermediate 107 9H-Fluoren-9-ylmethylN-({3-chloro-5-cyano-2-[(3-formylpyridin-2-yl) sulfanyl] phenyl} methyl)carbamate

To the stirred solution of 5-bromo-3-chloro-2-fluorobenzaldehyde (1.5 g,6.3 mmol) in NMP (11.5 ml) was added CuCN (680 mg, 7.59 mmol) and heatedat 170° C. for 30 min under microwave condition. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with water, brine solution, dried over sodiumsulfate and evaporated under reduced pressure to get the crude. Thecrude thus obtained was purified by normal silica column using 5-15%ethyl acetate in hexane to get 3-chloro-4-fluoro-5-formylbenzonitrile(562 mg, 48%) as yellow solid.

To a stirred solution of 2-mercapto nicotinic acid (1.4 g, 9.0 mmol) inDMF (15 mL) was added NaH (60%,0.393 g, 16.39 mmol) and reaction masswas stirred at 25° C. for 30 min. Then3-chloro-4-fluoro-5-formylbenzonitrile (1.5 g, 8.19 mmol) was added andreaction mixture was stirred at 70° C. for 4 h. Then K₂CO₃ (3.39 g,24.59 mmol) was added followed by addition of MeI (1.54 mL, 24.6 mmol)and reaction mass was stirred at 25° C. for 16 h. Reaction mass wasquenched with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude thusobtained was purified by normal silica column using 4-20% ethyl acetatein hexane to get methyl 2-[(2-chloro-4-cyano-6-formylphenyl)sulfanyl]pyridine-3-carboxylate (1.0 g, 36%) as a light yellow solid.

To a stirred solution of methyl2-[(2-chloro-4-cyano-6-formylphenyl)sulfanyl]pyridine-3-carboxylate (1.0g, 3.01 mmol) in THF (20 mL) were added 2-methylpropane-2-sulfinamide(365 mg, 3.01 mmol), Ti(OEt)₄ (3.15 ml, 15.06 mmol) and reaction masswas heated to 70° C. for 45 min. The reaction mass was quenched withsaturated sodium chloride solution, solid obtained was filtered throughcelite pad, washed with ethyl acetate. The separated organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford Ethyl2-[(2-chloro-4-cyano-6-{[(2-methylpropane-2-sulfinyl) imino] methyl}phenyl) sulfanyl] pyridine-3-carboxylate (1.2 g) which was directly usedfor next step without further purification. LC-MS: 449.8 [M+H]⁺.

To a stirred solution of ethyl2-[(2-chloro-4-cyano-6-{[(2-methylpropane-2-sulfinyl)imino]methyl}phenyl)sulfanyl]pyridine-3-carboxylate(1.3 g, 2.89 mmol) in THF (15 mL) was added LiBH4 (189.0 mg, 8.68 mmol)at 0° C. and reaction mass was heated to 70° C. for 2 h. Reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate. The separated organic layer was washedwith water, brine solution, dried over anhydrous sodium sulfate andevaporated under reduced pressure to get the crude. The crude thusobtained was purified by normal silica column using 0-60% ethyl acetatein hexane to getN-[(3-chloro-5-cyano-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamideas off-white solid (510 mg) as off white solid. LC-MS: 410.1 [M+H]⁺.

To a stirred solution ofN-[(3-chloro-5-cyano-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]-2-methylpropane-2-sulfinamide(510 mg, 1.25 mmol) in MeOH (8 mL), was added 4M HCl in dioxane (4 mL)at 0° C. and reaction mixture was stirred at 25° C. for 20 mins. Aftercompletion of reaction, reaction mixture was quenched with saturatedsodium bicarbonate solution, extracted with ethyl acetate, washed withbrine, dried over anhydrous sodium sulfate and concentrated under vacuumto get3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}benzonitrileHCl salt (350 mg, crude) which was directly used for next step. LC-MS:306.0 [M+H]⁺.

To a stirred suspension of 3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}benzonitrileHCl salt (350 mg, 1.15 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU(386.95 mg, 1.148 mmol) in dioxan (10 mL) at 25° C. and reaction masswas stirred at the same temperature for 16 h. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand evaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-5-cyano-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]carbamate(450 mg) which was directly used for next step. LC-MS: 528.1 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-5-cyano-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl)methyl]carbamate(450 mg, 0.85 mmol) in DCM:THF (1:1, 14 mL) was added MnO₂(1.48 g, 17.07mmol) and reaction mass was stirred at 25° C. for 1 h. The reaction masswas filtered through celite pad; filtrate was evaporated under reducedpressure. The crude thus obtained was purified by normal silica columnusing 20-40% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-5-cyano-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate(200 mg) as off-white solid with 94% LCMS purity. LC-MS: 525.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.15-4.38 (5H, m), 7.28-7.36 (2H, m), 7.42(2H, t, J=8.2 Hz), 7.68 (2H, d, J=7.9 Hz), 7.89 (2H, d, J=7.1 Hz),8.11-8.21 (1H, m), 8.36-8.48 (2H, m), 10.14-10.23 (1H, m).

Intermediate 108 9H-Fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl} phenyl} methyl)carbamate

To a stirred solution of N-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(500 mg, 0.86 mmol) in toluene (5 mL) were added2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (141 mg, 1.04 mmol) andsodium tertiary butoxide (333 mg, 3.46 mmol) and degassed in argonatmosphere for 5 min. Then to it were added 2-ditertiary butyl phosphinobiphenyl (23.3 mg, 0.078 mmol) and Pd(dba)₂ (39.9 mg, 0.07 mmol) andheated to 110° C. for 16 h. The reaction mass was filtered throughcelite pad and the filtrate was evaporated under reduced pressure. Thecrude thus obtained was purified by combiflash column chromatographyusing 5% methanol in dichloromethane to getN-({2-[(3-{[(tert-butyldimethylsilyl) oxy] methyl} pyridin-2-yl)sulfanyl]-3-chloro-5-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}phenyl}methyl)-2-methylpropane-2-sulfinamide(300 mg, 58%) as light yellow solid. LC-MS: 595.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}phenyl}methyl)-2-methylpropane-2-sulfinamide(900 mg, 1.51 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL)at 0° C. and reaction mixture was stirred at 25° C. for 2 h. Thereaction mass was evaporated under reduced pressure to get (2-{[2-(aminomethyl)-6-chloro-4-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}phenyl]sulfanyl}pyridin-3-yl)methanol hydrochloride (700 mg) which was directly used for next step.LC-MS: 377.6 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (700 mg, 1.85 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc-OSU(626 mg, 1.85 mmol) in dioxan (10 mL) at 25° C. and reaction mass wasstirred at the same temperature for 16 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-Fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl} phenyl)methyl] carbamate (800 mg) as off white solid, which was used for nextstep without further purification. LC-MS: 600.2 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}phenyl)methyl]carbamate(800 mg, 1.33 mmol) in DCM:THF (1:1, 20 mL) was added MnO₂ (2.32 g, 26.7mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 30%-80% ethylacetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}phenyl}methyl)carbamate(170 mg) as off white solid with 90.89% purity. LC-MS: 598.0 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 3.02 (1H, d, J=9.5 Hz), 3.44 (1H, d, J=10.1Hz), 3.64 (1H, d, J=7.1 Hz), 3.71 (1H, d, J=8.0 Hz), 4.22 (5H, dd,J=16.7, 6.3 Hz), 4.62 (2H, d, J=22.8 Hz), 6.56 (1H, s), 6.79 (1H, s),7.27-7.38 (3H, m), 7.42 (2H, t, J=6.9 Hz), 7.69 (2H, d, J=7.7 Hz),7.70-7.78 (1H, m), 7.89 (2H, d, J=7.7 Hz), 8.30 (1H, d, J=7.1 Hz), 8.43(1H, d, J=5.0 Hz), 10.20 (1H, s).

Intermediate 109 9H-fluoren-9-ylmethylN-({5-[3-(benzyloxy)prop-1-yn-1-yl]-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate

To a stirred and degassed suspension ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl) oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide (2 g,3.46 mmol), [(prop-2-yn-1-yloxy)methyl]benzene (1 mL, 6.9 mmol) intriethylamine (8 mL) were added CuI (13 mg, 0.07 mmol), palladiumacetate (8 mg, 0.04 mmol), PPh₃(18 mg, 0.07 mmol) and reaction mass washeated to 80° C. for 6 h. Reaction mass was evaporated under reducedpressure and the crude material obtained was purified by normal silicacolumn using 0-30% ethyl acetate in hexane to getN-({5-[3-(benzyloxy)prop-1-yn-1-yl]-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(1 g, 45%) as colourless sticky liquid. LC-MS: 643.2 [M+H]⁺.

To a stirred solution ofN-({5-[3-(benzyloxy)prop-1-yn-1-yl]-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide (1 g, 1.5mmol) in MeOH (8 mL), was added 4M HCl in dioxan (4 mL) at 0° C. andreaction mixture was stirred at 25° C. for 2 h. Reaction mass wasevaporated under reduced pressure to get(2-{[2-(aminomethyl)-4-[3-(benzyloxy)prop-1-yn-1-yl]-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (700 mg) which was directly used for next step. LC-MS: 425.1[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-4-[3-(benzyloxy)prop-1-yn-1-yl]-6-chlorophenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (700 mg, 1.5 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (511mg, 1.5 mmol) in dioxan (40 mL) at 25° C. and reaction mass was stirredat the same temperature for 2 h. Then the reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-({5-[3-(benzyloxy)prop-1-yn-1-yl]-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl}methyl)carbamate (850 mg) as off white solid which was used for next stepwithout further purification. LC-MS: 647.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-({5-[3-(benzyloxy)prop-1-yn-1-yl]-3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl}methyl)carbamate (850 mg, 1.31 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂(2.28 g, 26.3 mmol) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad and the filtrate wasevaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 10%-50% ethylacetate in hexane toget 9H-fluoren-9-ylmethylN-({5-[3-(benzyloxy)prop-1-yn-1-yl]-3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate (500 mg) as off white solid with 91%purity. LC-MS: 645.3 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.26-4.30 (5H, m), 4.49 (2H, s), 4.62 (2H,s), 7.30-7.42 (11H, m), 7.68 (3H, d, J=7.0 Hz), 7.88 (3H, d, J=7.1 Hz),8.38 (1H, d, J=7.6 Hz), 8.42 (1H, d, J=4.6 Hz), 10.19 (1H, s).

Intermediate 110 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(pyridin-4-yl)phenyl}methyl) carbamate

To a stirred solution of compoundN-({6-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(4 g, 6.93 mmol) in dioxan (30 mL) were added pyridine-4-boronic acid(1.1 g, 9.01 mmol), Na₂CO₃ (2.2 g, 20.79 mmol), water (15 mL) anddegassed for 10 min in argon atmosphere. Then to it was addedPd(PPh₃)₄(0.8 g, 0.69 mmol) and again degassed for 5 min. The reactionmass was heated to 120° C. for 16 h. Reaction mixture was then cooled to25° C., filtered through celite pad, washed with EtOAc. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand concentrated under vacuum to get the crude which was purified bynormal silica column using 5-80% ethyl acetate in hexane to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(pyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.2 g, 55%) as off white solid. LC-MS: 575.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(pyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2.2 g, 3.82 mmol) in MeOH (20 mL), was added 4M HCl in dioxan (10 mL)at 0° C. and reaction mixture was stirred at 25° C. for 2 h. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-3-(pyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.3 g) which was directly used for next step. LC-MS: 358.2[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-3-(pyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.3 g, 3.64 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.22 g, 3.64 mmol) in dioxan (20 mL) at 25° C. and reaction mass wasstirred at the same temperature for 16 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(pyridin-4-yl)phenyl)methyl]carbamate (2 g) which was directly used for next step.LC-MS: 580.2 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(pyridin-4-yl)phenyl)methyl]carbamate (2.0 g, 3.45 mmol) in DCM:THF (1:1, 40 mL) wasadded MnO₂ (6.0 g, 69 mmol) and reaction mass was stirred at 25° C. for2 h. The reaction mass was filtered through celite pad; filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 40-80% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(pyridin-4-yl)phenyl}methyl)carbamate (650 mg) as off white solid with 90% LCMS purity. LC-MS: 577.9[M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.10-4.14 (5H, m), 7.33-7.46 (8H, m), 7.58(1H, s), 7.65 (2H, d, J=7.3 Hz), 7.73 (1H, d, J=8.3 Hz), 7.89 (2H, d,J=7.4 Hz), 8.35 (1H, d, J=7.7 Hz), 8.48 (1H, d, J=3.1 Hz), 8.59 (2H, d,J=5.5 Hz), 10.21 (1H, s).

Intermediate 111 (RO7189173-000-001) 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(pyridin-3-yl)phenyl}methyl) carbamate

To a stirred solution of compoundN-({6-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(4 g, 6.9 mmol) in dioxan (40 mL) were added pyridine-3-boronic acid(1.1 g, 8.9 mmol), Na₂CO₃ (2.2 g, 20.7 mmol), water (20 mL) and degassedfor 10 min in argon atmosphere. Then to it was added Pd(PPh₃)₄(400 mg,0.34 mmol) and again degassed for 5 min. The reaction mass was heated to120° C. for 16 h. Reaction mixture was then cooled to 25° C., filteredthrough celite pad, washed with EtOAc. The separated organic layer waswashed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(pyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(4 g, crude) which was directly used for next step without furtherpurification. LC-MS: 575.6 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(pyridin-3-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(4 g, 6.9 mmol) in MeOH (40 mL), was added 4M HCl in dioxan (20 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-3-(pyridin-3-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (2.5 g) which was directly used for next step. LC-MS: 357.8[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-3-(pyridin-3-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (2.5 g, 6.3 mmol) in 5% NaHCO₃ (40 mL) was added Fmoc-OSU (2.13g, 6.3 mmol) in dioxan (80 mL) at 25° C. and reaction mass was stirredat the same temperature for 2 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(pyridin-3-yl)phenyl)methyl]carbamate(3 g) which was directly used for next step. LC-MS: 580.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(pyridin-3-yl)phenyl)methyl]carbamate(3 g, 5.17 mmol) in DCM:THF (1:1, 60 mL) was added MnO₂ (8.99 g, 103.4mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude thus obtained was purified by normal silicacolumn using 10-50% ethyl acetate in hexane to get 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(pyridin-3-yl)phenyl}methyl)carbamate (1.2 g) as off white solid with 89% LCMS purity. LC-MS: 577.7[M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.07-4.16 (5H, m), 7.29-7.50 (7H, m), 7.59(1H, s), 7.65 (2H, d, J=7.5 Hz), 7.72 (1H, d, J=8.3 Hz), 7.88 (3H, t,J=7.8 Hz), 8.34 (1H, d, J=6.3 Hz), 8.48 (1H, d, J=4.6 Hz), 8.61 (1H, d,J=4.1 Hz), 8.65 (1H, s), 10.21 (1H, s).

Intermediate 112 9H-Fluoren-9-ylmethylN-[[2-(2-formylphenyl)sulfanyl-6-morpholin-4-ylpyridin-3-yl]methyl]carbamate

To a solution of 2,6-dichloronicotinaldehyde (200 mg, 1.14 mmol, Eq: 1)and Et₃N (115 mg, 158 μl, 1.14 mmol, Eq: 1) in DMF (2.6 ml) was added asolution of morpholine (99 mg, 99.4 μl, 1.14 mmol, Eq: 1) in DMF (520μl). The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was concentrated in vacuo and the obtained2-chloro-6-morpholinonicotinaldehyde (350 mg yellow solid) was used inthe next step without further purification. MS ESI (m/z): 227.1[(M+H)⁺].

This material was prepared in analogy to Intermediate 68 starting from2-chloro-6-morpholinonicotinaldehyde and methyl 2-mercaptobenzoate. Thetitle compound was obtained as light yellow solid (50 mg). MS ESI (m/z):552.2 [(M+H)⁺].

Intermediate 113 (9H-Fluoren-9-yl)methyl((4-((2-formylphenyl)thio)-2-morpholinopyridin-3-yl)methyl)carbamate

To a stirred solution of methyl 2-sulfanylbenzoate (5 g, 29.72 mmol) inDMF (50 ml) was added Cs₂CO₃ (19.369 g, 59.45 mmol) followed by2,4-dichloropyridine-3-carbaldehyde (5.231 g 29.72 mmol) and heated at70° C. for 2 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith water, dried over anhydrous sodium sulfate and concentrated undervacuum. The crude, thus obtained was purified by silica gel columnchromatography using ethyl acetate in n-hexane (0-8%) as eluting solventto afford methyl 2-[(2-chloro-3-formylpyridin-4-yl)sulfanyl]benzoate(6.1 g, 66.69%) as light yellow solid. LC-MS: 307.9 [M+H]⁺.

To a stirred solution of methyl2-[(2-chloro-3-formylpyridin-4-yl)sulfanyl]benzoate (2.5 g, 8.12 mmol)in toluene (30 ml) were added Cs₂CO₃ (7.93 g, 24.35 mmol), morpholine(0.8 ml, 9.74 mmol) and purged with argon. Then xantphos (0.235 g, 0.41mmol), Pd₂(dba)₃ (0.372 g, 0.41 mmol) were added to the reactionmixture, again purged with argon and heated at 110° C. for 6 h. Thereaction mixture was quenched with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The crude, thusobtained was purified by silica gel column chromatography using ethylacetate in n-hexane (0-40%) as eluting solvent to afford methyl2-{[3-formyl-2-(morpholin-4-yl)pyridin-4-yl]sulfanyl}benzoate (2.1 g,72%) as white solid. LC-MS: 359.6 [M+H]⁺.

To a stirred solution of methyl2-{[3-formyl-2-(morpholin-4-yl)pyridin-4-yl]sulfanyl}benzoate (2.1 g,5.87 mmol) in THF (40 ml) were added 2-methylpropane-2-sulfinamide(0.711 g, 5.87 mmol) and Ti(OEt)₄ (6.2 ml, 29.33 mmol) and heated at 70°C. for 2 h. The reaction mixture was quenched with brine solution, ethylacetate was added and filtered. The aqueous layer was extracted withethyl acetate, dried the combined organic layers over anhydrous sodiumsulfate and concentrated under vacuum. The crude, thus obtained waspurified by combi flash column chromatography using ethyl acetate inhexane (0-40%) as eluting solvent to afford methyl2-({3-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-2-(morpholin-4-yl)pyridin-4-yl}sulfanyl)benzoate(690 mg, 26%) as yellow solid. LC-MS: 462.1 [M+H]⁺.

To a stirred solution of methyl2-({3-[(1E)-[(2-methylpropane-2-sulfinyl)imino]methyl]-2-(morpholin-4-yl)pyridin-4-yl}sulfanyl)benzoate(900 mg, 1.95 mmol) in THF (15 ml) was added LiAlH₄ (2M in THF, 1.95 ml,3.91 mmol) at 0° C. and stirred at 25° C. for 30 min. The reactionmixture was quenched with aqueous saturated sodium sulfate solution (15ml), filtered and concentrated under vacuum to affordN-[(4-{[2-(hydroxymethyl)phenyl]sulfanyl}-2-(morpholin-4-yl)pyridin-3-yl)methyl]-2-methylpropane-2-sulfinamide(720 mg, crude), which was used without further purification. LC-MS:435.7 [M+H]⁺.

To a stirred solution ofN-[(4-{[2-(hydroxymethyl)phenyl]sulfanyl}-2-(morpholin-4-yl)pyridin-3-yl)methyl]-2-methylpropane-2-sulfinamide (crude, 700 mg, 1.62 mmol) in MeOH(6 ml) was added 4N HCl in dioxane (10 ml) at 0° C. and stirred at 25°C. for 30 min. The reaction mixture was concentrated under vacuum toafford(2-{[3-(aminomethyl)-2-(morpholin-4-yl)pyridin-4-yl]sulfanyl}phenyl)methanolhydrochloride (670 mg, crude) as brown solid and was used withoutfurther purification. LC-MS: 332.4 [M+H]⁺.

To a stirred suspension of(2-{[3-(aminomethyl)-2-(morpholin-4-yl)pyridin-4-yl]sulfanyl}phenyl)methanol hydrochloride (crude, 650 mg, 1.64 mmol) in 5% aqueous NaHCO₃(5 ml) was added Fmoc-OSu (609.241 mg, 1.81 mmol) in dioxane (5 ml) andstirred at 25° C. for 30 min. The reaction mixture was filtered andconcentrated under vacuum. The crude, thus obtained was purified bysilica gel chromatography using ethyl acetate in n-hexane (0-40%) aseluting solvent to afford 9H-fluoren-9-ylmethylN-[(4-{[2-(hydroxymethyl)phenyl]sulfanyl}-2-(morpholin-4-yl)pyridin-3-yl)methyl]carbamate(700 mg, 65% over 3 steps) as white solid. LC-MS: 553.9 [M+H]⁺.

To a stirred suspension of 9H-fluoren-9-ylmethylN-[(4-{[2-(hydroxymethyl)phenyl]sulfanyl}-2-(morpholin-4-yl)pyridin-3-yl)methyl]carbamate(650 mg, 1.18 mmol) in DCM (10 ml) was added dess-martin periodinane(747.8 mg, 1.76 mmol) at 0° C. and stirred at 25° C. for 2 h. Thereaction mixture was diluted with DCM, washed with aqueous saturatedNaHCO₃ solution, followed by brine. The organic layer was separated,dried over anhydrous sodium sulfate and concentrated under vacuum. Thecrude, thus obtained was purified by silica gel column chromatographyusing ethyl acetate in n-hexane (0-40%) as eluting solvent to afford9H-fluoren-9-ylmethylN-({4-[(2-formylphenyl)sulfanyl]-2-(morpholin-4-yl)pyridin-3-yl}methyl)carbamate (230 mg, 36%) as white solid. LC-MS: 551.9 [M+H]⁺.

1H NMR: (400 MHz, DMSO-d6) δ 3.07 (4H, s), 3.70 (4H, s), 4.18-4.26 (1H,m), 4.32 (2H, d, J=6.6 Hz), 4.40-4.47 (2H, m), 6.41 (1H, d, J=5.3 Hz),7.28 (2H, t, J=6.7 Hz), 7.38 (2H, t, J=6.9 Hz), 7.48 (1H, d, J=7.7 Hz),7.65-7.77 (5H, m), 7.87 (2H, d, J=7.2 Hz), 7.99 (1H, d, J=6.4 Hz), 8.04(1H, d, J=5.2 Hz), 10.29 (1H, s).

Intermediate 114 (9H-Fluoren-9-yl)methyl((6-bromo-3-((3-formylpyridin-2-yl)thio)pyridin-2-yl)methyl)carbamate

This material was prepared in analogy to Intermediate 95 starting from6-bromo-3-fluoropicolinaldehyde and 2-mercaptonicotinic acid. The titlecompound was obtained as light red foam (133 mg). MS ESI (m/z): 546.0,548.0 [(M+H)⁺].

Intermediate 115[2-(4-Bromo-2-formyl-phenylsulfanyl)-3-chloro-benzyl]-carbamic acid9H-fluoren-9-ylmethyl ester

To a suspension of sodium sulfide, anhydrous (4.14 g, 2.23 ml, 53 mmol,Eq: 2) in DMF, anhydrous (100 ml) was added at 22° C. methyl3-chloro-2-fluorobenzoate (5.00 g, 26.5 mmol, Eq: 1), warmed to 70° C.while color changed to dark green and stirred at 70° C. for 2 h whilecolor changed to yellow to give complete conversion. The mixture wascooled to 5° C. and quenched by dropping slowly into an ice-cold 10%HCl-solution (200 ml), diluted with sat NaCl (200 ml) and extracted withethyl acetate (2×300 ml). The organic layers were dried and evaporatedto give a yellow oil. The crude product was purified by flashchromatography (silica gel, 80 g, adsorbed on Isolute HM-N, EtOAc inheptane 0% to 10% to 50%) to give methyl 3-chloro-2-mercaptobenzoate(2.95 g, 55%) as a light yellow oil.

To a solution of methyl 3-chloro-2-mercaptobenzoate (2.5 g, 12.3 mmol,Eq: 1) in DMF (50 ml) was added at 22° C. 5-bromo-2-fluorobenzaldehyde(3.76 g, 18.5 mmol, Eq: 1.5) followed by potassium carbonate (1.7 g,12.3 mmol, Eq: 1), warmed to 70° C. and stirred at 70° C. for 3 h togive conversion complete. The suspension was cooled to 22° C., theprecipitated solid was filtered off, washed with ether (1×15 ml). Thefiltrate was evaporated and the yellow turbid oil was purified by flashchromatography (silica gel, 120 g, adsorbed on Isolute sorbent HM-N,EtOAc in heptane 0% to 30%) to give methyl2-((4-bromo-2-formylphenyl)thio)-3-chlorobenzoate (2.536 g, 53%) as alight yellow solid.

LC-MS: m/z=385.0 (M+H)+ (monoisotopic mass 383.92)

To a solution of methyl2-((4-bromo-2-formylphenyl)thio)-3-chlorobenzoate (2.41 g, 6.25 mmol,Eq: 1) in toluene (72 ml) was added at 22° C. ethylene glycol (776 mg,697 μl, 12.5 mmol, Eq: 2) followed by p-toluenesulfonic acid monohydrate(119 mg, 625 μmol, Eq: 0.1), heated to reflux with a Dean-Stark-trap andstirred at 111° C. (oil bath 145° C.) for 10 h, but only 72% conversionby LC-MS. Further addition of 1.4 ml ethylene glycol (=4 eq) followed byan additional 119 mg (=0.1 eq) p-toluenesulfonic acid monohydrate andagain stirring at reflux as described for 4 h gave more impurities(LC-MS) and no further conversion. The solvent was removed under reducedpressure, the residue was treated with sat NaHCO₃ (100 ml) and extractedwith ethyl acetate (2×100 ml). The organic layers were dried andevaporated. The residue was purified by flash chromatography (silicagel, 120 g, adsorbed on Isolute HM-N, Hep/DCM 2:1 to 100% DCM) to givemethyl 2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorobenzoate(2.257 g, 84%) as a colorless oil.

LC-MS: m/z=429.0 (M+H)+ (for monoisotopic mass 427.95)

To a solution of methyl2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorobenzoate (2.2 g,5.12 mmol, Eq: 1) in tetrahydrofuran (44 ml) was added dropwise at 0° C.lithium aluminum hydride, 2 M in THF (7.68 ml, 15.4 mmol, Eq: 3) andstirred at 0° C. for 3 h to give complete conversion. The mixture wasquenched by dropwise addition of 2.5 ml water (ca. 2.5 eq—exotherm, gasevolution) and stirred for 1 h at 0° C. Then allowed to warm to 22° C.,treated with Na2SO4 and diluted with ethyl acetate (16 ml) and filteredoff. The filtrate was evaporated and dried to give the title compound(1.711 g, 83%) as colorless oil. Used as is in next step.

LC-MS: 69% with m/z=339.1 (M+H−ethylene glycole)+ for product (formonoisotopic mass 399.95) and 20% impurity with m/z=261.0 (M+H−ethyleneglycole)+ for desbromo-byproduct.

To a solution of(2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorophenyl)methanol(1.65 g, 4.11 mmol, Eq: 1) in dichloromethane (17 ml) was added at 0° C.triethylamine (1.25 g, 1.72 ml, 12.3 mmol, Eq: 3) followed dropwise (5minutes) by methanesulfonyl chloride (706 mg, 480 μl, 6.16 mmol, Eq:1.5) while internal temperature was kept below 5° C. and stirred at 0°C. for 30 min to give complete conversion. The mixture was quenched withwater (50 ml) and extracted with dichloromethane (2×50 ml). The organiclayers were dried and evaporated. The residue was purified by flashchromatography (silica gel, 80 g, adsorbed on Isolute HM-N, EtOAc inheptane 0% to 50%) to give2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorobenzylmethanesulfonate (1.132 g, 57%) as a colorless oil.

LC-MS: m/z=479.0 (M+H)+ (477.93 for monoisotopic mass)

To a solution of2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorobenzylmethanesulfonate (1.05 g, 2.19 mmol, Eq: 1) in Tetrahydrofuran (8 ml)was added at −78° C. ammonia (11.2 g, 14.2 ml, 657 mmol, Eq: 300) viacondensation at −78° C. and followed by transfer into dry-ice coldautoclave via funnel, closed and allowed to warm to 22° C. After total 2h the autoclave was again cooled to ca. −50° C., valve opened andallowed to warm while excess ammonia was absorbed into wash-bottlecontaining 5 M HCl. The remaining reaction mixture was purged with argonfor 20 minutes and the mixture was filtered. The filtrate was evaporatedto give(2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorophenyl)methanamine(715 mg, 82%) as colorless oil.

LC-MS: m/z=400.0 (M+H)+ (398.97 for monoisotopic mass) To an emulsion of(2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorophenyl)methanamine(660 mg, 1.65 mmol, Eq: 1) in sodium bicarbonate, 5% aq (8.3 g, 7.69 ml,4.94 mmol, Eq: 3) was added at 22° C. a solution of(9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (556 mg,1.65 mmol, Eq: 1) in Acetonitrile (6.6 ml) and stirred at 22° C. for 2h. The organic solvent was removed under reduced pressure, diluted withwater (10 ml) and extracted with ethyl acetate (2×20 ml). The organiclayers were washed with sat NaCl (1×20 ml), dried and evaporated. Theresidue was purified by flash chromatography (silica gel, 24 g, adsorbedon Isolute HM-N, EtOAc in heptane 0% to 30%) to give(9H-fluoren-9-yl)methyl2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorobenzylcarbamate(920 mg, 90%) as a white foam.

LC-MS: m/z=622.0 (M+H)+ (621.04 for monoisotopic mass)

To a solution of (9H-fluoren-9-yl)methyl2-((4-bromo-2-(1,3-dioxolan-2-yl)phenyl)thio)-3-chlorobenzylcarbamate(872 mg, 1.4 mmol, Eq: 1) in Acetone (26 ml) was added at 22° C.hydrochloric acid, 5 M aq (11.2 ml, 56 mmol, Eq: 40) and stirred at 22°C. for 2 h while a solid precipitated to give complete conversion. Themixture was concentrated under reduced pressure to half volume and thesolid was filtered off, washed with acetonitrile (1×5 ml), pentane (2×5ml) and dried in HV to give (9H-fluoren-9-yl)methyl2-((4-bromo-2-formylphenyl)thio)-3-chlorobenzylcarbamate (785 mg, 97%)as a white solid.

LC-MS: m/z=560.0 (M+H-H2O)+ (MW 577.0 for monoisotopic mass)

1H NMR (400 MHz, CDCl₃) δ 10.25 (s, 1H), 7.96 (m, 1H), 7.76 (m, 3H),7.52 (br s, 3H), 7.41 (m, 6H), 7.28 (m, 3H), 6.45 (br d, J=8.5 Hz, 1H),5.22 (br t, J=5.9 Hz, 1H), 4.50 (m, 2H), 4.39 (d, J=6.9 Hz, 2H), 4.15(m, 2H).

Intermediate 116 9H-fluoren-9-ylmethylN-{[3-chloro-5-(4-cyanophenyl)-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 3.46 mmol) in dioxan (20 mL) were added (4-cyanophenyl)boronicacid (661 mg, 4.49 mmol), Na₂CO₃ (1.1 g, 10.38), and degassed for 10 minin argon atmosphere. Then to it was added Pd(PPh₃)₄(200 mg, 0.17 mmol)and again degassed for 10 min. The reaction mass was heated to 120° C.for 16 h. Reaction mixture was then cooled to 25° C., filtered throughcelite pad, washed with EtOAc. The separated organic layer was washedwith brine solution, dried over sodium sulfate and concentrated underreduced pressure. The crude thus obtained was purified by silica columnchromatography (SiO₂; 100-200 mesh; 0%-30% ethyl acetate in hexane) togetN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4-cyanophenyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.4 g, 67%) as off white solid. LC-MS: 600.2 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(4-cyanophenyl)phenyl}methyl)-2-methylpropane-2-sulfinamide(1.4 g, 2.33 mmol) in MeOH (8 mL), was added 4M HCl in dioxan (4 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get4-[3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]benzonitrilehydrochloride (1 g) which was directly used for next step withoutfurther purification. LC-MS: 381.7 [M+H]⁺.

To a stirred suspension of4-[3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]benzonitrilehydrochloride (1 g, 2.39 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(0.81 g, 2.39 mmol) in dioxan (40 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-{[3-chloro-5-(4-cyanophenyl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(1.6 g) as off white solid; which was used for next step without furtherpurification. LC-MS: 604.1 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[3-chloro-5-(4-cyanophenyl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(1.6 g, 2.65 mmol) in DCM:THF (1:1, 80 mL) was added MnO₂ (4.6 g, 52.97mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude material obtained was purified by silicacolumn chromatography (SiO₂; 100-200 mesh; 10%-50% EtOAc/Hexane) to get9H-fluoren-9-ylmethylN-{[3-chloro-5-(4-cyanophenyl)-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate(730 mg) as a off white solid with 97% LCMS purity. LC-MS: 602.1 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.20 (1H, d, J=6.8 Hz), 4.27 (2H, d, J=7.1Hz), 4.37 (2H, d, J=5.5 Hz), 7.25 (2H, t, J=7.5 Hz), 7.39 (3H, q, J=7.8,6.9 Hz), 7.66 (2H, d, J=7.2 Hz), 7.74 (1H, s), 7.89 (3H, t, J=7.6 Hz),7.97 (5H, q, J=8.9 Hz), 8.38 (1H, d, J=7.6 Hz), 8.44 (1H, d, J=4.4 Hz),10.22 (1H, s).

Intermediate 117 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(2-methylpyridin-4-yl)phenyl}methyl)carbamate

To a stirred solution of compoundN-({6-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(3 g, 5.18 mmol) in dioxan (20 mL) were added(2-methylpyridin-4-yl)boronic acid (924 mg, 6.74 mmol), Na₂CO₃ (1.65 g,15.56 mmol), water (10 mL) and degassed for 10 min in argon atmosphere.Then to it was added Pd(PPh₃)₄(300 mg, 0.25 mmol) and again degassed for10 min. The reaction mass was heated to 120° C. for 16 h. The reactionmass was filtered through celite pad and filtrate was evaporated underreduced pressure to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(2-methylpyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(3 g) as off white solid. LC-MS: 589.7 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(2-methylpyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(3 g, 5.08 mmol) in MeOH (12 mL), was added 4M HCl in dioxan (6 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-3-(2-methylpyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanol(1.7 g) which was directly used for next step without furtherpurification. LC-MS: 371.9 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-3-(2-methylpyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanol(1.7 g, 4.16 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU (1.4 g, 4.16mmol) in dioxan (40 mL) at 25° C. and reaction mass was stirred at thesame temperature for 2 h. Then reaction mass was diluted with water andextracted with ethyl acetate. The separated organic layer was washedwith brine solution, dried over sodium sulfate and evaporated underreduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(2-methylpyridin-4-yl)phenyl)methyl]carbamate(2 g, crude) as off white solid; which was used for next step withoutfurther purification. LC-MS: 593.6 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-6-(2-methylpyridin-4-yl)phenyl)methyl]carbamate(2.0 g, 3.36 mmol) in DCM:THF (1:1, 60 mL) was added MnO₂ (5.85 g, 67.32mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad; filtrate was evaporated under reducedpressure. The crude thus obtained was purified by silica columnchromatography (SiO₂; 100-200 mesh; 10%-50% EtOAc/Hexane) to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-6-(2-methylpyridin-4-yl)phenyl}methyl)carbamate (650 mg, 21%, 4 steps) as off white solid with94.83% purity. LC-MS: 591.7 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 2.43 (3H, s), 4.12 (5H, s), 7.25 (1H, d,J=4.8 Hz), 7.28-7.35 (4H, m), 7.33-7.40 (1H, m), 7.39 (1H, d, J=4.3 Hz),7.43 (2H, d, J=8.1 Hz), 7.60 (1H, s), 7.66 (2H, d, J=7.4 Hz), 7.71 (1H,d, J=8.3 Hz), 7.89 (2H, d, J=7.5 Hz), 8.35 (1H, d, J=7.6 Hz), 8.44 (1H,d, J=5.0 Hz), 8.47 (1H, d, J=3.5 Hz), 10.21 (1H, s).

Intermediate 118 (RO7125868-000-001) 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyrimidin-5-yl)phenyl}methyl)carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(650 mg, 1.13 mmol) in toluene (7 mL) were added4-(tributylstannyl)pyrimidine (623 mg, 1.69 mmol) and LiCl (14 mg, 0.034mmol) and degassed in argon atmosphere for 10 min. Then to it was addedPd(PPh3)4 (130.1 mg, 0.11 mmol) and reaction mass was heated to 110° C.for 16 h. Reaction mixture was then filtered through celite pad andevaporated under reduced pressure. The crude thus obtained was purifiedby normal silica column using 1-8% methanol in DCM to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyrimidin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (260 mg, 40%) as lightyellow solid. LC-MS: 576.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyrimidin-4-yl)phenyl} methyl)-2-methylpropane-2-sulfinamide (260 mg, 0.45 mmol) inMeOH (8 mL), was added 4M HCl in dioxan (4 mL) at 0° C. and reactionmixture was stirred at 25° C. for 2 h. The reaction mass was evaporatedunder reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyrimidin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (200 mg) which was directly used for next step. LC-MS: 358.9[M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(pyrimidin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (200 mg, 0.56 mmol) in 5% NaHCO₃ (5 mL) was added Fmoc-OSU (188mg, 0.56 mmol) in dioxan (5 mL) at 25° C. and reaction mass was stirredat the same temperature for 2 h. Then reaction mass was diluted withwater and extracted with ethyl acetate. The separated organic layer waswashed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyrimidin-4-yl)phenyl)methyl]carbamate(250 mg) as off white solid. LC-MS: 581.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyrimidin-4-yl)phenyl)methyl]carbamate(250 mg, 0.43 mmol) in DCM:THF (1:1, 10 mL) was added MnO₂ (749.3 mg,8.62 mmol) and reaction mass was stirred at 25° C. for 2 h. The reactionmass was filtered through celite pad and the filtrate was evaporatedunder reduced pressure. The crude material obtained was purified bynormal silica column using 30-80% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyrazin-2-yl)phenyl}methyl)carbamate(145 mg) as off white solid with 96% LCMA purity. LC-MS: 578.8 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.23 (1H, dd, J=5.0, 1.2 Hz), 4.28 (2H, d,J=6.5 Hz), 4.38 (2H, d, J=5.4 Hz), 7.28 (2H, t, J=6.5 Hz), 7.40 (3H, t,J=6.6 Hz), 7.69 (2H, d, J=7.4 Hz), 7.89 (2H, d, J=7.6 Hz), 7.95-8.03(1H, m), 8.18 (1H, d, J=5.2 Hz), 8.26 (1H, s), 8.34 (1H, s), 8.39 (1H,d, J=7.8 Hz), 8.42-8.47 (1H, m), 8.95 (1H, d, J=5.2 Hz), 9.25 (1H, s),10.22 (1H, s).

Intermediate 119 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(4-sulfamoylphenyl)phenyl}methyl)carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(3 g, 5.19 mmol) in dioxan (30 mL) were added (4-sulfamoylphenyl)boronicacid (1.35 g, 6.7 mmol), Na₂CO₃ (1.65 g, 15.5 mmol), water (15 mL) anddegassed for 10 min in argon atmosphere. Then to it was addedPd(PPh₃)₄(300 mg, 0.26 mmol) and again degassed for 5 min. The reactionmass was heated to 120° C. for 16 h. Reaction mixture was then cooled to25° C., filtered through celite pad and washed with EtOAc. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand concentrated under reduced pressure to get4-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-{[(2-methylpropane-2-sulfinyl)amino]methyl}phenyl}benzene-1-sulfonamide(3 g) as colourless sticky liquid. LC-MS: 654.0 [M+H]⁺.

To a stirred solution of4-{4-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-{[(2-methylpropane-2-sulfinyl)amino]methyl}phenyl}benzene-1-sulfonamide(3 g, 4.58 mmol) in MeOH (12 mL), was added 4M HCl in dioxan (6 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get4-[3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]benzene-1-sulfonamidehydrochloride (2.2 g) which was directly used for next step. LC-MS:435.7 [M+H]⁺.

To a stirred suspension of4-[3-(aminomethyl)-5-chloro-4-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]benzene-1-sulfonamidehydrochloride (2 g, 4.23 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.43 g, 4.23 mmol) in dioxan (40 mL) at 25° C. and reaction mass wasstirred at the same temperature for 2 h. Then reaction mass was dilutedwith water and extracted with 10% methanol in dichloromethane. Theseparated organic layer was washed with brine solution, dried oversodium sulfate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(4-sulfamoylphenyl)phenyl)methyl]carbamate (2.5 g) as off white solid. LC-MS: 657.9 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(4-sulfamoylphenyl)phenyl)methyl]carbamate (2.5 g, 3.8 mmol) in DCM/THF (1:1, 60 mL) wasadded MnO₂ (6.6 g, 75.9 mmol) and reaction mass was stirred at 25° C.for 2 h. The reaction mass was filtered through celite pad and filtratewas evaporated under reduced pressure. The crude material obtained waspurified by silica column (SiO₂; 100-200 mesh; 10-50% ethyl acetate inhexane) to give 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(4-sulfamoylphenyl)phenyl}methyl)carbamate(520 mg) as off white solid with 95% LCMS purity. LC-MS: 654.2 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.21 (1H, d, J=6.5 Hz), 4.28 (2H, d, J=6.8Hz), 4.37 (2H, d, J=5.7 Hz), 7.25 (2H, t, J=7.4 Hz), 7.39 (4H, q, J=7.4Hz), 7.48 (2H, s), 7.67 (2H, d, J=7.5 Hz), 7.72 (1H, s), 7.89 (4H, dd,J=12.8, 7.0 Hz), 7.93-8.02 (1H, m), 8.38 (1H, d, J=6.3 Hz), 8.45 (1H, d,J=3.4 Hz), 10.22 (1H, s).

Intermediate 120 (9H-fluoren-9-yl)methyl2-((5-bromo-2-formylphenyl)thio)-3-chlorobenzylcarbamate

To a suspension of sodium sulfide, anhydrous (2.46 g, 1.32 ml, 31.5mmol, Eq: 2) in DMF, anhydrous (73 ml) was added at 22° C. methyl4-bromo-2-fluorobenzoate (3.67 g, 15.7 mmol, Eq: 1), warmed to 70° C.while color changed to brown and stirred at 70° C. for 2 h to givecomplete conversion. The mixture was cooled to 5° C. and quenched bydropping slowly into an ice-cold 10% HCl-solution (100 ml), diluted withsat NaCl (100 ml) while internal temperature was kept below 10° C. andextracted with ethyl acetate (2×100 ml). The organic layers were driedand evaporated to give a yellow semi-solid. The crude product waspurified by flash chromatography (silica gel, 80 g, adsorbed on IsoluteHM-N, EtOAc in heptane 5% to 10% to 20% to 60%) to give methyl4-bromo-2-mercaptobenzoate (1.29 g, 33%) as a light yellow oil.

LC-MS: m/z=245.0 (M−H)⁻ (MW 245.94 for monoisotopic mass)

To a solution of methyl 4-bromo-2-mercaptobenzoate (1.29 g, 5.22 mmol,Eq: 1) in DMF (25.8 ml) was added at 22° C.3-chloro-2-fluorobenzaldehyde (1.24 g, 7.83 mmol, Eq: 1.5) followed bypotassium carbonate (721 mg, 5.22 mmol, Eq: 1), warmed to 70° C. andstirred at 70° C. for 30 min to give nearly conversion complete. Thesuspension was cooled to 22° C., the precipitated solid was filtered off(dicalite) and washed with ether (1×15 ml). The filtrate was evaporatedin HV and the yellow oil was purified by flash chromatography (silicagel, 80 g, EtOAc in heptane 0% to 20% to 60%) to give methyl4-bromo-2-((2-chloro-6-formylphenyl)thio)benzoate (1.73 g, 86%) as alight yellow solid.

LC-MS: m/z=385.0 (M+H)+ (monoisotopic mass 383.92)

To a solution of methyl4-bromo-2-((2-chloro-6-formylphenyl)thio)benzoate (1.73 g, 4.49 mmol,Eq: 1) and 2-methylpropane-2-sulfinamide (544 mg, 4.49 mmol, Eq: 1) inTHF (19 ml) was added at 22° C. Titanium(IV)ethoxide (5.12 g, 4.65 ml,22.4 mmol, Eq: 5) to give a clear yellow solution followed by heating toreflux and stirred at 70° C. for 1 h to give complete conversion. Thelight turbid yellow suspension was cooled to 22° C. and quenched withsat NaCl (25 ml) to give a thick suspension. The mixture was filteredthrough dicalite and washed with ethyl acetate (2×25 ml). The filtrate(2-phase-system) was transferred into a separation funnel, the aqueouslayer was separated and the organic layer was dried and evaporated togive a mix of (E)-methyl4-bromo-2-((2-(((tert-butylsulfinyl)imino)methyl)-6-chlorophenyl)thio)benzoateand (E)-ethyl4-bromo-2-((2-(((tert-butylsulfinyl)imino)methyl)-6-chlorophenyl)thio)benzoate(2.16 g, 97%) as a light yellow foam.

NMR: mixture of methyl- and ethyl-ester ratio ca. 7:4.

LC-MS: m/z=488.1 and 502.1 (M+H)+ (MW for monoisotopic mass: 486.97 and500.98)

To a solution of (E)-methyl4-bromo-2-((2-(((tert-butylsulfinyl)imino)methyl)-6-chlorophenyl)thio)benzoateand (E)-ethyl4-bromo-2-((2-(((tert-butylsulfinyl)imino)methyl)-6-chlorophenyl)thio)benzoate(ratio 7:4, 2.16 g, 4.42 mmol, Eq: 1) in THF (21.6 ml) was added at 22°C. lithium borohydride (963 mg, 44.2 mmol, Eq: 10) while color changedimmediately to intensive green and internal temperature rised up to 31°C. The mixture was warmed to 50° C. and stirred at 50° C. for 20 h togive complete conversion. The mixture was cooled to 22° C., quencheddropwise (effervescensing and exothermic—cooling with ice-water bath)with sat NH4Cl (100 ml) and completely extracted with ethyl acetate(1×50 ml) by stirring for 30 minutes until gas evolution has ceased. Theorganic layer was washed with 5% KH2PO4 (1×50 ml, pH 5) and sat. NaCl(1×50 ml), dried and evaporated to give the crude product as whitesolid. The solid was suspended in 20 ml ethyl acetate under reflux, Theoil bath was removed, 20 ml heptane was added in one portion and cooledto 22° C. while solid precipitated. The suspension was cooled to 5° C.and stirred for 60 minutes, the solid was filtered off, washed withEtOAc/Hep 1:1 (1×10 ml) and dried in HV to giveN-(2-((5-bromo-2-(hydroxymethyl)phenyl)thio)-3-chlorobenzyl)-2-methylpropane-2-sulfinamide(1.538 g, 75%) as white solid.

LC-MS: m/z=462.1 (M+H)+ for monoisotopic mass 460.99

To a suspension ofN-(2-((5-bromo-2-(hydroxymethyl)phenyl)thio)-3-chlorobenzyl)-2-methylpropane-2-sulfinamide(1.478 g, 3.19 mmol, Eq: 1) in Methanol (14.8 ml) was added at 0° C.HCl, 4 M in dioxane (7.98 ml, 31.9 mmol, Eq: 10), allowed to warm to 22°C. while solid dissolved completely and stirred at 22° C. for 30 min togive complete conversion. After total 60 minutes the solvent was removedunder reduced pressure and dried in HV to give(2-((2-(aminomethyl)-6-chlorophenyl)thio)-4-bromophenyl)methanolhydrochloride (1.26 g, 100%) as white solid.

LC-MS: m/z=358.0 (M+H)+ (free amine MW 356.96 for monoisotopic mass)

To a solution of(2-((2-(aminomethyl)-6-chlorophenyl)thio)-4-bromophenyl)methanolhydrochloride (1.23 g, 3.11 mmol, Eq: 1) in Methanol (73.4 ml) was addedat 22° C. pyridine (985 mg, 1.01 ml, 12.5 mmol, Eq: 4) followed by(9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.1 g,3.27 mmol, Eq: 1.05) and stirred at 22° C. for 3 days while more solidhad precipitated to give conversion complete. The solid was filteredoff, washed with methanol (2×15 ml) and dried in HV to give(9H-fluoren-9-yl)methyl2-((5-bromo-2-(hydroxymethyl)phenyl)thio)-3-chlorobenzylcarbamate (1.538g, 85%) as white solid.

LC-MS: m/z=562.2 (M+H-H2O)+ (MW 579.03 for monoisotopic mass)

To a solution of (9H-fluoren-9-yl)methyl2-((5-bromo-2-(hydroxymethyl)phenyl)thio)-3-chlorobenzylcarbamate (1.485g, 2.56 mmol, Eq: 1) in THF (50 ml) and DCM (50 ml) was added at 22° C.manganese dioxide (4.44 g, 51.1 mmol, Eq: 20) and stirred at 22° C. for3 h to give conversion complete. The mixture was filtered(membrane-filter), washed with THF/DCM 1:1 (2×15 ml) and the filtratewas evaporated to give the product as yellow solid. The crude productwas suspended in 15 ml MeOH (ultrasonic bath for 30 minutes and thensuspended at 22° C. for 30 minutes), the solid was filtered off, washedwith MeOH (2×6 ml), dried in HV to give (9H-fluoren-9-yl)methyl2-((5-bromo-2-formylphenyl)thio)-3-chlorobenzylcarbamate (1.287 g, 87%)as off-white solid.

LC-MS: m/z=578.0 (M+H)+ for monoisotopic mass 577.01

1H NMR (600 MHz, DMSO-d₆) δ 10.15 (s, 1H), 7.95 (d, J=8.2 Hz, 1H),7.86-7.91 (m, 2H), 7.66-7.69 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.57-7.64(m, 2H), 7.37-7.44 (m, 2H), 7.37-7.40 (m, 1H), 7.33 (tJ, =7.5 Hz, 2H),6.52 (s, 1H), 4.31 (dd, J=9.8, 6.5 Hz, 4H), 4.20 (br d, J=6.5 Hz, 1H).

Intermediate 121 9H-fluoren-9-ylmethylN-{[3-chloro-6-(2-fluoropyridin-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl] phenyl]methyl}carbamate

To a stirred solution ofN-({6-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(4.0 g, 6.93 mmol) in dioxan (30 mL) were added(2-fluoropyridin-4-yl)boronic acid (1.17 g, 8.3 mmol), Na₂CO₃ (2.2 g,20.8 mmol), water (15 mL) and degassed for 10 min in argon atmosphere.Then to it was added Pd(PPh₃)₄(801 mg, 0.69 mmol) and again degassed for5 min. The reaction mass was heated to 120° C. for 16 h. Reactionmixture was then cooled to 25° C., filtered through celite pad andwashed with EtOAc. The separated organic layer was washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to get the crude which was purified by column chromatography(SiO₂; 100-200 mesh; 40-80% EtOAc/Hexane) to getN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(2-fluoropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 48%) as light yellow sticky solid. LC-MS: 593.8 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-6-(2-fluoropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 3.37 mmol) in THF (20 mL), was added 4M HCl in dioxan (10 mL) at0° C. and reaction mixture was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-3-(2-fluoropyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.2 g) which was directly used for next step withoutfurther purification. LC-MS: 376.0 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-3-(2-fluoropyridin-4-yl)phenyl]sulfanyl}pyridin-3-yl)methanolhydrochloride (1.2 g, 3.2 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.08 g, 3.2 mmol) in dioxan (20 mL) at 25° C. and reaction mass wasstirred at the same temperature for 16 h. Then reaction mass was dilutedwith water and extracted with 10% methanol in dichloromethane. Theseparated organic layer was washed with brine solution, dried oversodium sulfate and evaporated under reduced pressure to9H-fluoren-9-ylmethylN-{[3-chloro-6-(2-fluoropyridin-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamate(2 g) as off-white solid; which was used for next step without furtherpurification. LC-MS: 597.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-{[3-chloro-6-(2-fluoropyridin-4-yl)-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}phenyl]methyl}carbamatein DCM:THF (1:1, 30 mL) was added MnO₂ (5.82 g, 67.0 mmol) and reactionmass was stirred at 25° C. for 2 h. The reaction mass was filteredthrough celite pad and the filtrate was evaporated under reducedpressure. The crude thus obtained was purified by column chromatography(SiO₂; 100-200 mesh; 40-80% EtOAc/Hexane) to get 9H-fluoren-9-ylmethylN-{[3-chloro-6-(2-fluoropyridin-4-yl)-2-[(3-formylpyridin-2-yl)sulfanyl]phenyl]methyl}carbamate (610 mg) as off-white solid with 90%LCMS purity. LC-MS: 596.0 [M+H]⁺.

1H NMR (400 MHz, DMSO-d6): δ 4.10 (3H, s), 4.14-4.19 (2H, m), 7.27-7.51(8H, m), 7.59 (1H, s), 7.64 (2H, d, J=7.4 Hz), 7.74 (1H, d, J=8.3 Hz),7.82-7.98 (2H, m), 8.25 (1H, d, J=4.7 Hz), 8.35 (1H, d, J=6.2 Hz),8.44-8.49 (1H, m), 10.20 (1H, s).

Intermediate 122 9H-fluoren-9-ylmethylN-[[5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a stirred solution ofN-[[5-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.46 mmol) in 1,4-dioxane (20 mL) were added tert-butylN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate(1.44 g, 4.5 mmol), Na₂CO₃(11 mg, 0.1 mmol), water (10 mL) and reactionmass was purged with argon for 15 min. Then Pd(PPh₃)₄(0.2 g, 0.17 mmol)was added and reaction mass was heated to 120° C. in a sealed tube for16 h. Reaction mass was filtered through celite pad and the filtrate wasevaporated under reduced pressure to getN-[[5-(2-amino-4-pyridyl)-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g) as brown resin. LC-MS: 590.7 [M+H]⁺.

To a stirred solution ofN-[[5-(2-amino-4-pyridyl)-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.38 mmol) in THF (10 mL) was added 4M HCl in dioxan (10 mL,mmol) and reaction mass was stirred at 25° C. for 2 h. Reaction mass wasevaporated under reduced pressure to get[2-[2-(aminomethyl)-4-(2-amino-4-pyridyl)-6-chloro-phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.2 g) as off white solid. LC-MS: 373.0[M+H]⁺.

To a stirred suspension of[2-[2-(aminomethyl)-4-(2-amino-4-pyridyl)-6-chloro-phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.2 g, 2.93 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(988.8 mg, 2.93 mmol) in 1,4-dioxane (30 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand evaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 5-80% ethyl acetate in hexane toget 9H-fluoren-9-ylmethylN-[[5-(2-amino-4-pyridyl)-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(1.4 g) as off white solid. LC-MS: 594.7[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[5-(2-amino-4-pyridyl)-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(1.4 g, 2.35 mmol) in tert-butanol (10 mL) was added BOC anhydride (2.7mL, 11.76 mmol) and the reaction mass was stirred at 25° C. for 16 h.The reaction mass was evaporated under reduced pressure and crude thusobtained was purified by normal silica column using 5-40% ethyl acetatein hexane to get 9H-fluoren-9-ylmethylN-[[5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(850 mg) as off white solid. LC-MS: 695.2[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(850 mg, 1.22 mmol) DCM:THF (1:1, 40 mL) was added MnO₂ (2.13 g, 24.45mmol) and the reaction mass was stirred at 25° C. for 2 h. The reactionmass was filtered through celite pad and the filtrate was evaporatedunder reduced pressure. The crude material obtained was purified bynormal silica column using 10-50% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(425 mg) as a off white solid. LC-MS: 693.1 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 1.42 (9H; s); 4.27-4.36 (5H, m), 7.22-7.25(m; 2H); 7.35-7.40 (4H; m); 7.64-7.87 (2H; m); 7.85-7.87 (2H; m); 7.94(1H; m); 8.09 (1H; s); 8.34-8.39 2H; m); 8.46 (1H; m); 9.94 (1H; s);10.21 (1H, s).

Intermediate 123 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(4-sulfamoylphenyl)phenyl]methyl]carbamate

To a stirred solution ofN-[[6-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.46 mmol) in 1,4-dioxane (20 mL) were added(4-aminosulfonylphenyl)boronic acid (904 mg, 4.5 mmol), sodium carbonate(1.1 g, 10.38 mmol), water (10 mL) and the reaction mass was purged withargon for 15 min. Then Pd(PPh3)4 (2 mg, 0.002 mmol) was added and thereaction mass was heated to 120° C. in a sealed tube for 16 h. Reactionmass was filtered through celite pad and filtrate was evaporated underreduced pressure to get4-[3-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-2-[(tert-butylsulfinylamino)methyl]-4-chloro-phenyl]benzenesulfonamide(2 g) as brown resin. LC-MS: 654.1 [M+H]⁺.

To a stirred solution of4-[3-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-2-[(tert-butylsulfinylamino)methyl]-4-chloro-phenyl]benzenesulfonamide(2.0 g, 3.06 mmol) in THF (20 mL) was added 4M HCl in dioxan (8.0 mL, 32mmol) and the reaction mass was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get4-[2-(aminomethyl)-4-chloro-3-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]benzenesulfonamidehydrochloride (1.3 g) as off white solid. LC-MS: 435.8 [M+H]⁺.

To a stirred suspension of4-[2-(aminomethyl)-4-chloro-3-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]benzenesulfonamidehydrochloride (1.3 g, 2.75 mmol) in 5% NaHCO₃ (20.0 mL) was addedFmoc-OSU (0.93 g, 2.75 mmol) in 1,4-dioxane (30 mL) at 25° C. andreaction mass was stirred at the same temperature for 2 h. Then reactionmass was diluted with water and extracted with ethyl acetate. Theseparated organic layer was washed with brine solution, dried oversodium sulfate and evaporated under reduced pressure to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(4-sulfamoylphenyl)phenyl]methyl]carbamate (1.5 g) as off white solid. LC-MS: 657.9[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(4-sulfamoylphenyl)phenyl]methyl]carbamate(1.5 g, 2.28 mmol) in DCM:THF (1:1, 30 mL) was added MnO₂ (3.96 g, 45.58mmol) and the reaction mass was stirred at 25° C. for 2 h. The reactionmass was filtered through celite pad and the filtrate was evaporatedunder reduced pressure. The crude material obtained was purified bynormal silica column using 10-50% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(4-sulfamoylphenyl)phenyl]methyl]carbamate(640 mg) as a off white solid.

LC-MS: 656.0 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 4.13-4.11 (5H, m), 7.31-7.45 (7H; m);7.5-7.72 (5 h: m); 7.86-7.90 (4H; m); 8.35 (1H; m); 8.48 (1H; m); 10.21(1H, s).

Intermediate 124 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(4-methylsulfonylphenyl)phenyl] methyl]carbamate

To a stirred solution ofN-[[6-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.46 mmol) in 1,4-dioxane (20 mL) were added4-(methylsulfonyl)phenylboronic acid (0.9 g, 4.5 mmol), sodium carbonate(1.1 g, 10.38 mmol), water (10 mL) and the reaction mass was purged withargon for 15 min. Pd(PPh3)4 (0.2 g, 0.17 mmol) was added and reactionmass was heated to 120° C. in a sealed tube for 16 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure to getN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-6-(4-methylsulfonylphenyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g) as a brown resin.

LC-MS: 653.2 [M+H]⁺.

To a stirred solution ofN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-6-(4-methylsulfonylphenyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.06 mmol) in THF (20 mL) was added 4M HCl in dioxan (8.0 mL, 32mmol) and reaction mass was stirred at 25° C. for 2 h. Reaction mass wasevaporated under reduced pressure to get[2-[2-(aminomethyl)-6-chloro-3-(4-methylsulfonylphenyl)phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.4 g) as off white solid. LC-MS: 434.7 [M+H]⁺.

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-3-(4-methylsulfonylphenyl)phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.4 g, 2.97 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.0 g, 2.97 mmol) in 1,4-dioxane (40 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with 10% methanol in DCM. The separatedorganic layer was washed with brine, dried over sodium sulfate andevaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(4-methylsulfonylphenyl)phenyl]methyl]carbamate(1.8 g) as off white solid. LC-MS: 656.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(4-methylsulfonylphenyl)phenyl]methyl]carbamate(1.8 g, 2.74 mmol) in DCM:THF (1:1, 80 mL) was added MnO₂ (4.76 g, 54.78mmol) and reaction mass was stirred at ° C. for 2 h. Reaction mass wasfiltered through celite pad and the filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 10-50% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(4-methylsulfonylphenyl)phenyl]methyl]carbamate (920 mg) as a off white solid. LC-MS: 654.9[M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 3.18 (3H; s); 4.03-4.11 (5H, m), 7.30-7.38(3H; m); 7.38-7.45 (3H; m); 7.58 (1H; m); 7.64-7.71 (5 h; m); 7.89 (2H;m); 7.95-7.97 (2H; m); 8.35 (1H; br d; J=7.04 Hz); 8.48 (1H; m); 10.20(1H, s).

Intermediate 125 (9H-Fluoren-9-yl)methyl2-((5-fluoro-3-formylpyridin-2-yl)thio)benzylcarbamate

To a stirred solution of methyl 2-sulfanylbenzoate (2.5 g, 14.86 mmol)in DMF (30 ml) were added Cs₂CO₃ (7.267 g, 22.29 mmol) followed by2-chloro-5-fluoropyridine-3-carbaldehyde (2.371 g, 14.86 mmol) andheated at 70° C. for 30 min. The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined organic layers werewashed with water, dried over anhydrous sodium sulfate and concentratedunder vacuum. The crude thus obtained, was purified by silica gel columnchromatography using ethyl acetate in n-hexane (0-6%) as an elutingsolvent to afford methyl2-[(5-fluoro-3-formylpyridin-2-yl)sulfanyl]benzoate (2.65 g, 61%) as offwhite solid. LC-MS: 292.0 [M+H]⁺.

To a stirred solution of methyl2-[(5-fluoro-3-formylpyridin-2-yl)sulfanyl]benzoate (2.6 g, 8.93 mmol)in toluene (50 ml) were added ethylene glycol (1.5 ml, 26.78 mmol),p-TSA (0.17 g, 0.89 mmol) and heated at 100° C. for 2 h. The reactionmixture was filtered and concentrated under vacuum. The crude, thusobtained was purified by silica gel chromatography using ethyl acetatein n-hexane (0-10%) as eluting solvent to afford methyl2-{[3-(1,3-dioxolan-2-yl)-5-fluoro pyridin-2-yl]sulfanyl}benzoate (2.26g, 75%) as light yellow liquid. LC-MS: 335.7 [M+H]⁺.

To a stirred solution of methyl2-{[3-(1,3-dioxolan-2-yl)-5-fluoropyridin-2-yl]sulfanyl}benzoate (1.5 g,4.47 mmol) in THF (15 ml) was added LiBH₄ (0.292 g, 13.42 mmol) at 0° C.and heated at 60° C. for 4 h. The reaction mixture was quenched withsaturated aqueous ammonium chloride solution, diluted with water andextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The crude,thus obtained was purified by silica gel column chromatography usingethyl acetate in n-hexane (0-10%) as eluting solvent to afford(2-{[3-(1,3-dioxolan-2-yl)-5-fluoropyridin-2-yl]sulfanyl}phenyl)methanol(855 mg, 62%) as off white solid. LC-MS: 308.1 [M+H]⁺.

To a stirred solution of(2-{[3-(1,3-dioxolan-2-yl)-5-fluoropyridin-2-yl]sulfanyl}phenyl)methanol(250 mg, 0.81 mmol) in THF (5 ml) was added DPPA (0.3 ml, 1.22 mmol)followed by DBU (0.2 ml, 1.22 mmol) and stirred at 25° C. for 15 h. Thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under vacuum. The crude, thus obtained waspurified by silica gel column chromatography using ethyl acetate inn-hexane (0-8%) as eluting solvent to afford2-{[2-(azidomethyl)phenyl]sulfanyl}-3-(1,3-dioxolan-2-yl)-5-fluoropyridine(200 mg, 74%) as light yellow liquid. LC-MS: 332.9 [M+H]⁺.

To a stirred solution of2-{[2-(azidomethyl)phenyl]sulfanyl}-3-(1,3-dioxolan-2-yl)-5-fluoropyridine(200 mg, 0.60 mmol) in 2-propanol (5 ml) were added 1,3-propanedithiol(6.5 ml, 0.06 mmol), Et₃N (0.2 ml, 1.20 mmol), NaBH₄ (34 mg, 0.90 mmol)and stirred at 25° C. for 2 h.

The reaction mixture was concentrated under vacuum. The crude, thusobtained was purified by amine silica gel column chromatography usingethyl acetate in n-hexane as eluting solvent to afford(2-{[3-(1,3-dioxolan-2-yl)-5-fluoropyridin-2-yl]sulfanyl}phenyl)methanamine(125 mg, 68%) as colorless liquid. LC-MS: 306.8 [M+H]⁺.

To a stirred suspension of[2-[[3-(1,3-dioxolan-2-yl)-5-fluoro-2-pyridyl]sulfanyl]phenyl]methanamine(400 mg, 1.31 mmol) in 5% aqueous NaHCO₃ (5 ml) was added Fmoc-OSu(440.44 mg, 1.31 mmol) in acetonitrile (8 ml) and stirred at 25° C. for4 h. The reaction mixture was diluted with water and extracted withethyl acetate. The combined organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The crude, thus obtainedwas purified by combi flash column chromatography using ethyl acetate inn-hexane (0-10%) as eluting solvent to afford 9H-fluoren-9-ylmethylN-[[2-[[3-(1,3-dioxolan-2-yl)-5-fluoro-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(330 mg, 47.82% yield) as white solid. LC-MS: 528.8 [M+H]⁺.

To a solution of 9H-fluoren-9-ylmethylN-[[2-[[3-(1,3-dioxolan-2-yl)-5-fluoro-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(485 mg, 0.920 mmol) in acetone (15 ml) was added aqueous HCl (12N, 3ml, 36 mmol) and the reaction mixture was stirred at 25° C. for 4 h. Thereaction mixture was concentrated under vacuum, diluted the residue withwater (10 ml), quenched with aqueous saturated sodium bicarbonatesolution (10 ml) and extracted with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated undervacuum. The crude, thus obtained was purified by silica gel columnchromatography using ethyl acetate in n-hexane (0-8%) as eluting solventto afford 9H-fluoren-9-ylmethyl N-({2-[(5-fluoro-3-formylpyridin-2-yl)sulfanyl]phenyl}methyl)carbamate (146 mg, 33% yield) aswhite solid. LC-MS: 484.9 [M+H]⁺.

1H NMR: (400 MHz, DMSO-d) δ 4.20 (3H, d, J=5.6 Hz), 4.31 (2H, d, J=6.8Hz), 7.31-7.35 (4H, m), 7.41 (2H, d, J=7.4 Hz), 7.49 (2H, dd, J=15.3,7.3 Hz), 7.69 (2H, d, J=7.3 Hz), 7.76 (1H, t, J=4.5 Hz), 7.89 (2H, d,J=7.2 Hz), 8.31 (1H, dd, J=8.6, 2.7 Hz), 8.54 (1H, d, J=3.2 Hz), 10.19(1H, s).

Intermediate 126 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-5-imidazol-1-yl-phenyl]methyl]carbamate

To a stirred solution ofN-[[5-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(500 mg, 0.86 mmol) in 1,4-dioxane (10 mL) was added Imidazole (70.66mg, 1.04 mmol), K3PO4 (0.37 g, 1.73 mmol) and DMEDA (0.04 mL, 0.35 mmol)and degassed in argon atmosphere for 5 min. Then to it was added CuI(32.94 mg, 0.17 mmol) and heated at 110° C. for 16 h. Reaction mixturewas then extracted with ethyl acetate and the separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get crude which was purified by columnchromatography (1%-10% MeOH in DCM) to affordN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-5-imidazol-1-yl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(125 mg) as light yellow solid. LC-MS: 565.0 [M+H]⁺.

To a stirred solution ofN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-5-imidazol-1-yl-phenyl]methyl]-2-methyl-propane-2-sulfinamide(500 mg, 0.88 mmol) in THF (10 mL) was added 4M HCl in dioxan (4.0 mL,16 mmol) and the reaction mass was stirred at 25° C. for 2 h. Thereaction mass was evaporated under reduced pressure to get[2-[2-(aminomethyl)-6-chloro-4-imidazol-1-yl-phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (300 mg) as light brown resin. LC-MS: 346.9 [M+H]⁺.

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-4-imidazol-1-yl-phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (300 mg, 0.78 mmol) in 5% NaHCO₃ (10 mL) was addedFmoc-OSU (264 mg, 0.78 mmol) in 1,4-dioxane (20 mL) at 25° C. and thereaction mass was stirred at the same temperature for 2 h. Then reactionmass was diluted with water and extracted with ethyl acetate. Theseparated organic layer was washed with brine, dried over sodium sulfateand evaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-imidazol-1-yl-phenyl]methyl]carbamate.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-imidazol-1-yl-phenyl]methyl]carbamate(400 mg, 0.7 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (1222 mg,14.06 mmol) and the reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad and the filtrate wasevaporated under reduced pressure. The crude material obtained waspurified by normal silica column using 0-3% methanol in DCM to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-5-imidazol-1-yl-phenyl]methyl]carbamate(127 mg) as off white solid. LC-MS: 566.7 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 4.02-4.08 (1H, m), 4.19-4.28 (2H, m),4.28-4.48 (2H, m) 7.18 (1H; m); 7.27-7.26 (2H, m), 7.35-7.39 (3H, m),7.65-7.67 (2H, m), 7.81-7.82 (2H, m), 7.85-7.86 (2H; m); 7.89-7.90 (1H;m); 8.36-8.43 (3H; m); 10.21 (1H, s).

Intermediate 127 9H-fluoren-9-ylmethylN-[[6-[6-(tert-butoxycarbonylamino)-3-pyridyl]-3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a stirred solution ofN-[[6-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.46 mmol) in 1,4-dioxane (20 mL) were added2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (989.8mg, 4.5 mmol), sodium carbonate (1.1 g, 10.38 mmol), water (10 mL) andreaction mass was purged with argon for 15 min. Then Pd(PPh3)4 (199.97mg, 0.170 mmol) was added and reaction mass was heated to 120° C. in asealed tube for 16 h. The reaction mass was filtered through celite padand the filtrate was evaporated under reduced pressure to getN-[[6-(6-amino-3-pyridyl)-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g) as light brown resin. LC-MS: 590.7 [M+H]⁺.

To a stirred solution ofN-[[6-(6-amino-3-pyridyl)-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.38 mmol) in THF (20 mL) was added 4M HCl in dioxane (10.0 mL,40 mmol) and the reaction mass was stirred at 25° C. for 2 h. Thereaction mass was evaporated under reduced pressure to get[2-[2-(aminomethyl)-3-(6-amino-3-pyridyl)-6-chloro-phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.3 g) as light yellow solid. LC-MS: 372.8 [M+H]⁺.

To a stirred suspension of[2-[2-(aminomethyl)-3-(6-amino-3-pyridyl)-6-chloro-phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.3 g, 3.18 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.07 g, 3.18 mmol) in 1,4-dioxane (40 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with 10% methanol in DCM. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand evaporated under reduced pressure. The crude thus obtained waspurified by normal silica column using 0-5% methanol in DCM to get9H-fluoren-9-ylmethylN-[[6-(6-amino-3-pyridyl)-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(1.2 g) as a off white solid. LC-MS: 594.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[6-(6-amino-3-pyridyl)-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(1.2 g, 2.02 mmol) in tert-butanol (10 mL) was added BOC anhydride (2.32mL, 10.08 mmol) and reaction mass was stirred at 25° C. for 16 h. Thereaction mass was evaporated under reduced pressure and crude thusobtained was purified by normal silica column using 5-40% ethyl acetatein hexane to get 9H-fluoren-9-ylmethylN-[[6-[6-(tert-butoxycarbonylamino)-3-pyridyl]-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(800 mg, 1.15 mmol) as off white solid. LC-MS: 695.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[6-[6-(tert-butoxycarbonylamino)-3-pyridyl]-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(800 mg, 1.15 mmol) in DCM:THF (1:1, 40 mL) was added MnO₂ (2.0 g, 23.01mmol) and the reaction mass was stirred at 25° C. for 2 h. The reactionmass was filtered through celite pad and the filtrate was evaporatedunder reduced pressure. The crude material obtained was purified bynormal silica column using 10-50% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[6-[6-(tert-butoxycarbonylamino)-3-pyridyl]-3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate(420 mg) as a off white solid. LC-MS: 693.1 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 1.46 (9H; s); 4.27-4.36 (5H, m), 7.22-7.25(7H; m); 7.57-7.70 (4H; m); 7.80-7.89 (4H; m); 8.30-8.35 (2H; m); 8.47(1H; m); 9.91 (1H; s); 10.21 (1H; s).

Intermediate 128 9H-fluoren-9-ylmethylN-[[3-chloro-5-(2-cyano-4-pyridyl)-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate

To a stirred solution of compoundN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(2 g, 3.46 mmol) in dioxan (20 mL) were added4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (1.03 g,4.5 mmol), Na₂CO₃ (1.1 g, 10.3 mmol) and degassed for 10 min in argonatmosphere. Then to it was added Pd(PPh₃)₄(200 mg, 0.173 mmol) and againdegassed for 10 min. The reaction mass was heated to 120° C. for 16 h.The reaction mixture was then cooled to 25° C., filtered through celitepad, washed with EtOAc. The separated organic layer was washed withbrine, dried over sodium sulfate and concentrated under reducedpressure. The crude thus obtained was purified by silica columnchromatography (SiO₂; 100-200 mesh; 10%-60% ethyl acetate in hexane) togetN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-5-(2-cyano-4-pyridyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide (850 mg) as yellow solid.LC-MS: 600.9 [M+H]⁺.

To a stirred solution ofN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-5-(2-cyano-4-pyridyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide (850 mg, 1.41 mmol) in THF(20 mL), was added 4M HCl in dioxan (10 mL) at 0° C. and reactionmixture was stirred at 25° C. for 2 h. The reaction mass was evaporatedunder reduced pressure to get4-[3-(aminomethyl)-5-chloro-4-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]pyridine-2-carbonitrilehydrochloride (550 mg) which was directly used for next step withoutfurther purification. LC-MS: 382.7 [M+H]⁺.

To a stirred suspension of4-[3-(aminomethyl)-5-chloro-4-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]pyridine-2-carbonitrilehydrochloride (550 mg, 1.31 mmol) in 5% NaHCO₃ (20 mL) was addedFmoc-OSU (442 mg, 1.31 mmol) in dioxan (20 mL) at 25° C. and reactionmass was stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with 10% methanol in DCM. The separatedorganic layer was washed with brine, dried over sodium sulfate andevaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-[[3-chloro-5-(2-cyano-4-pyridyl)-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(750 mg) as off white solid, which was used for next step withoutfurther purification. LC-MS: 605.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-5-(2-cyano-4-pyridyl)-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(750 mg, 1.24 mmol) in DCM:THF (1:1, 60 mL) was added MnO₂ (2.15 g,24.79 mmol) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad and the filtrate wasevaporated under reduced pressure. The crude thus obtained was purifiedby silica column chromatography (SiO₂; 100-200 mesh; 10%-50% ethylacetate in hexane) to get 9H-fluoren-9-ylmethylN-[[3-chloro-5-(2-cyano-4-pyridyl)-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate (430 mg) as a off white solid. LC-MS:603.1 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 4.02-4.08 (1H, m), 4.19-4.28 (2H, m),4.28-4.29 (2H, m) 7.27-7.26 (2H, m), 7.35-7.39 (2H, m), 7.65-7.67 (2H,m), 7.86-7.87 (4H, m), 8.11-8.12 (1H; m); 8.14-8.15 (1H; m); 8.38-8.40(1H; m); 8.40-8.41 (1H; m); 8.51-8.52 (1H; m); 8.78 (1H; br d; J=7.2 Hz)10.21 (1H, s).

Intermediate 129 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(6-hydroxy-3-pyridyl)phenyl]methyl]carbamate

To a stirred solution ofN-[[6-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.46 mmol) in 1,4-dioxane (20 mL) were added(6-hydroxypyridine-3-yl)boronic acid (0.62 g, 4.5 mmol), sodiumcarbonate (1.1 g, 10.38 mmol), water (10 mL) and reaction mass waspurged with argon for 15 min. Then Pd(PPh3)4 (199.97 mg, 0.17 mmol) wasadded and reaction mass was heated to 120° C. in a sealed tube for 16 h.The reaction mass was filtered through celite pad and filtrate wasevaporated under reduced pressure to getN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-6-(6-hydroxy-3-pyridyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g) as light yellow gum. LC-MS: 592.1. [M+H]⁺.

To a stirred solution ofN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-6-(6-hydroxy-3-pyridyl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.38 mmol) in THF (20 mL) was added 4M HCl in dioxane (12.0 mL,48 mmol) and reaction mass was stirred at 25° C. for 2 h. Reaction masswas evaporated under reduced pressure to get5-[2-(aminomethyl)-4-chloro-3-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]pyridin-2-olhydrochloride (1.3 g) as off white solid. LC-MS: 374.0 [M+H]⁺.

To a stirred suspension of5-[2-(aminomethyl)-4-chloro-3-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]pyridin-2-olhydrochloride (1.3 g, 3.18 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.07 g, 3.18 mmol) in 1,4-dioxane (40 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with 10% methanol in DCM. The separatedorganic layer was washed with brine solution, dried over sodium sulfateand evaporated under reduced pressure to get 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(6-hydroxy-3-pyridyl)phenyl]methyl]carbamate(1.5 g) as a light yellow solid. LC-MS: 596.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-6-(6-hydroxy-3-pyridyl)phenyl]methyl]carbamate(1.5 g, 2.52 mmol) in DCM/THF (1:1, 40 mL) was added MnO2 (4.37 g, 50.33mmol) and the reaction mass was stirred at 25° C. for 2 h. The reactionmass was filtered through celite pad and the filtrate was evaporatedunder reduced pressure. The crude material obtained was purified bynormal silica column using 0-3% methanol in DCM to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-6-(6-hydroxy-3-pyridyl)phenyl]methyl]carbamate(140 mg) as off white solid.

LC-MS: 593.9 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 4.13-4.19 (5H, m), 7.32-7.34 (3H, m),7.40-7.42 (4H, m), 7.49-7.52 (2H, m), 7.65-7.67 (3H, m), 7.82 (2H, brd,J=6.92 Hz), 8.34 (1H, brd, J=5.2 Hz), 8.45 (1H, s), 10.20 (1H, s), 11.81(1H, s).

Intermediate 130 9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-5-(1H-pyrrol-3-yl)phenyl]methyl]carbamate

To a stirred solution ofN-[[5-bromo-2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.46 mmol) in 1,4-dioxane (20 mL) were added tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1-carboxylate(1.32 g, 4.5 mmol), sodium carbonate (1.1 g, 10.38 mmol), water (10 mL)and the reaction mass was purged with argon for 15 min. Then Pd(PPh3)4(199.89 mg, 0.17 mmol) was added and reaction mass was heated to 120° C.in a sealed tube for 16 h. The reaction mass filtered through celite padand filtrate evaporated under reduced pressure to getN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-5-(1H-pyrrol-3-yl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2 g) as yellow resin

LC-MS: 564.3. [M+H]⁺.

To a stirred solution ofN-[[2-[[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]sulfanyl]-3-chloro-5-(1H-pyrrol-3-yl)phenyl]methyl]-2-methyl-propane-2-sulfinamide(2.0 g, 3.54 mmol) in tetrahydrofuran (10 mL) was added 4M HCl in dioxan(6.0 mL, 24 mmol) and the reaction mixture was stirred at 25° C. for 2h. The reaction mass was evaporated under reduced pressure to get[2-[2-(aminomethyl)-6-chloro-4-(1H-pyrrol-3-yl)phenyl]sulfanyl-3-pyridyl]methanol hydrochloride (1.3 g) as off whitesolid. LC-MS: 345.8 [M+H]⁺.

To a stirred suspension of[2-[2-(aminomethyl)-6-chloro-4-(1H-pyrrol-3-yl)phenyl]sulfanyl-3-pyridyl]methanolhydrochloride (1.3 g, 3.4 mmol) in 5% NaHCO₃ (20 mL) was added Fmoc-OSU(1.15 g, 3.4 mmol) in 1,4-dioxane (40 mL) at 25° C. and reaction masswas stirred at the same temperature for 2 h. Then reaction mass wasdiluted with water and extracted with ethyl acetate. The separatedorganic layer was washed with brine, dried over sodium sulfate andevaporated under reduced pressure to 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-(1H-pyrrol-3-yl)phenyl]methyl]carbamate(1.5 g) as a off white solid. LC-MS: 568.0 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-5-(1H-pyrrol-3-yl)phenyl]methyl]carbamate(1.5 g, 2.64 mmol) in DCM/THF (1:1, 60 mL) was added MnO₂ (4.59 g, 52.81mmol) and reaction mass was stirred at 25° C. for 2 h. The reaction masswas filtered through celite pad and the filtrate was evaporated underreduced pressure. The crude material obtained was purified by normalsilica column using 10-50% ethyl acetate in hexane to get9H-fluoren-9-ylmethylN-[[3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]-5-(1H-pyrrol-3-yl)phenyl]methyl]carbamate(535 mg) as light yellow solid.

LC-MS: 566.1 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 4.19-4.28 (5H, m), 6.48 (1H; brs); 6.85(1H; brs); 7.28-7.29 (2H; m); 7.32-7.37 (2H; m); 7.47-7.42 (2H; m); 7.53(1H; brs); 7.69-7.70 (3H; m); 7.81-7.83 (1H; m); 7.88 (2H; d; J=7.44Hz); 8.34 (1H; d; J=7.0 Hz); 8.34 (1H; brs); 10.21 (1H, s); 11.13 (1H;s).

Intermediate 131 (9H-Fluoren-9-yl)methyl2-((5-bromo-3-formylpyridin-2-yl)thio)benzylcarbamate

This material was prepared in analogy to Intermediate 125 starting from5-bromo-2-chloro-pyridine-3-carbaldehyde and methyl thiosalicylate,except for the last step which was performed as follows.

To a solution of 9H-fluoren-9-ylmethylN-[[2-[[5-bromo-3-(1,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate(800 mg, 1.36 mmol) in acetone (15 ml) and water (3 ml) was addedpyridinium p-toluenesulfonate (204.62 mg, 0.810 mmol) and the reactionmixture was heated at 60° C. for 25 h. The reaction mixture wasconcentrated under vacuum, diluted the residue with water (20 ml),quenched with 5% aqueous saturated sodium bicarbonate solution (10 ml)and extracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The crude,thus obtained was purified by silica gel column chromatography usingethyl acetate in n-hexane (0-8%) as eluting solvent to afford9H-fluoren-9-ylmethylN-[[2-[(5-bromo-3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate (120mg, 27% yield) as off white solid. LC-MS: 545.2 [M+H]⁺.

1H NMR: (400 MHz, DMSO-d6) δ 4.19 (3H, d, J=5.8 Hz), 4.30 (2H, d, J=7.0Hz), 7.34 (4H, d, J=7.1 Hz), 7.42 (2H, t, J=7.5 Hz), 7.49 (2H, dd,J=12.8, 7.1 Hz), 7.69 (2H, d, J=7.7 Hz), 7.75 (1H, t, J=5.8 Hz), 7.89(2H, d, J=7.2 Hz), 8.58 (2H, s), 10.13 (1H, s).

Intermediate 132 (9H-Fluoren-9-yl)methyl((2-(dimethylamino)-4-((3-formylpyridin-2-yl)thio)pyridin-3-yl)methyl)carbamate

To a stirred solution of 2-mercaptonicotinic acid (10 g, 64.45 mmol) inDMSO (40 ml) was added trifluoroacetic acid (0.49 ml, 6.44 mmol) at 0°C. and the reaction mixture was heated at 60° C. for 24 h. The reactionmixture was then cooled to 0° C., DMF (100 ml) and Potassium carbonate(8.91 g, 64.45 mmol) were then added and stirred for 30 min at 0° C.Then iodomethane (12.04 ml, 193.34 mmol) was slowly added at 0° C. andthe reaction mixture was stirred at 25° C. for 16 h. Reaction mixturewas then cooled to 0° C., a solution of acetic acid (13 ml) in water(150 ml) was added slowly and the resulting mixture stirred at 25° C.for 6 h. Precipitated white solid was filtered, washed with water (3×70ml) followed by hexane (3×30 ml), dried under vacuum to afford methyl2-[(3-methoxycarbonyl-2-pyridyl)disulfanyl]pyridine-3-carboxylate (8.24g, crude) as white solid which was used without further purification.LC-MS: 336.6 [M+H]⁺.

To a stirred solution of methyl2-[(3-methoxycarbonyl-2-pyridyl)disulfanyl]pyridine-3-carboxylate (8.2g, 24.38 mmol) in 1,4-dioxane (34 ml) were added triphenyl phosphine(8.95 g, 34.13 mmol) and water (18 ml) successively at 25° C. and heatedat 65° C. for 16 h. The reaction mixture was concentrated under vacuum.The residue thus obtained was diluted with EtOH (85 ml) and heated at75° C. for 15 min. Reaction mixture was then cooled to 25° C. slowlyfollowed by to 0° C. by 4 h. Solid was then collected by filtration anddried well under vacuum to afford methyl2-sulfanylpyridine-3-carboxylate (7.54 g, 69.17% yield over 2 steps) asyellow solid. LC-MS: 170.1 [M+H]⁺.

To a stirred solution of methyl 2-sulfanylpyridine-3-carboxylate (800mg, 4.73 mmol) in DMF (8 ml) was added potassium carbonate (1306.91 mg,9.46 mmol) at 0° C. in portions and stirred for 15 min. Then2-chloro-4-fluoro-pyridine-3-carbaldehyde (829.81 mg, 5.2 mmol) in DMF(2 ml) was added slowly at the same temperature and slowly allowed toreach 25° C. and stirred for 2 h. After completion of reaction, reactionmixture was cooled to 0° C., quenched with acetic acid (0.5 ml),followed by water (12 ml) and stirred at 25° C. for 1 h. The yellowsolid thus precipitated, was collected by filtration, washed withn-hexane and then dried under vacuum to afford methyl2-[(2-chloro-3-formyl-4-pyridyl)sulfanyl]pyridine-3-carboxylate (1.05 g,71.93% yield) as yellow solid. LC-MS: 308.8 [M+H]⁺.

In a sealed tube, to a stirred solution of methyl2-[(2-chloro-3-formyl-4-pyridyl)sulfanyl]pyridine-3-carboxylate (1.0 g,3.24 mmol) in 1,4-dioxane (10 ml) was added dimethyl amine (2M in THF,16.19 ml, 32.39 mmol) and heated at 120° C. for 12 h. The reactionmixture was concentrated under vacuum. The crude, thus obtained waspurified by silica gel chromatography using ethyl acetate in n-hexane(0-30%) as eluting solvent to afford methyl2-[[2-(dimethylamino)-3-formyl-4-pyridyl]sulfanyl]pyridine-3-carboxylate(930 mg, 90.47%) as yellow solid. LC-MS: 317.8 [M+H]⁺.

To a stirred solution of methyl2-[[2-(dimethylamino)-3-formyl-4-pyridyl]sulfanyl]pyridine-3-carboxylate(910 mg, 2.87 mmol) in tetrahydrofuran (20 ml) were added2-methyl-2-propanesulfinamide (347.53 mg, 2.87 mmol) and titanium(IV)ethoxide (1.8 ml, 8.6 mmol) and heated at 70° C. for 2 h. The reactionmixture was quenched with brine (30 ml), ethyl acetate (50 ml) was addedand filtered. The aqueous layer was extracted with ethyl acetate, thecombined organic layers dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude, thus obtained was purified bysilica gel column chromatography using ethyl acetate in hexane (0-20%)as eluting solvent to afford ethyl2-[[3-[(E)-tert-butylsulfinyliminomethyl]-2-(dimethylamino)-4-pyridyl]sulfanyl]pyridine-3-carboxylate(1.22 g, crude, mixture of ethyl and isopropylester) as brown viscousliquid which was used without further purification. LC-MS: 434.6, 448.6[M+H]⁺.

To a stirred solution of ethyl2-[[3-[(E)-tert-butylsulfinyliminomethyl]-2-(dimethylamino)-4-pyridyl]sulfanyl]pyridine-3-carboxylate(1.2 g, 2.76 mmol) in tetrahydrofuran (15 ml) was slowly added lithiumaluminium hydride (2M in THF, 2.7 ml, 5.52 mmol) at 0° C. The reactionmixture was then slowly allowed to reach 25° C. and stirred for 30 min.Then the reaction mixture was quenched with aqueous saturated sodiumsulfate solution (25 ml), diluted with ethyl acetate (50 ml) andfiltered. The aqueous layer was then extracted with ethyl acetate, thecombined organic layers dried over anhydrous sodium sulfate andconcentrated under vacuum to affordN-[[2-(dimethylamino)-4-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-pyridyl]methyl]-2-methyl-propane-2-sulfinamide(1.01 g, crude) as light brown liquid, which was used without furtherpurification. LC-MS: 394.8 [M+H]⁺.

To a stirred solution ofN-[[2-(dimethylamino)-4-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-pyridyl]methyl]-2-methyl-propane-2-sulfinamide(1 g, 2.53 mmol) in methanol (10 ml) was added hydrogen chloride (4 M indioxane) (15.0 ml) at 0° C. The reaction mixture was then allowed toreach 25° C. and stirred for 30 min. Then the reaction mixture wasconcentrated under vacuum to afford[2-[[3-(aminomethyl)-2-(dimethylamino)-4-pyridyl]sulfanyl]-3-pyridyl]methanolhydrochloride (805 mg, crude) as off white solid, which was used withoutfurther purification. LC-MS: 291.2 [M+H]⁺.

To a stirred solution of[2-[[3-(aminomethyl)-2-(dimethylamino)-4-pyridyl]sulfanyl]-3-pyridyl]methanolhydrochloride (800 mg, 2.45 mmol) in aqueous 5% NaHCO₃ (15.0 ml, 2.45mmol) was added Fmoc-OSu (825.68 mg, 2.45 mmol) in acetonitrile (20 ml)and stirred at 25° C. for 1 h. The reaction mixture was diluted withwater (10 ml) and extracted with ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated undervacuum. The crude, thus obtained was purified by trituration with 30%ethyl acetate in n-hexane to afford 9H-fluoren-9-ylmethylN-[[2-(dimethylamino)-4-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-pyridyl]methyl]carbamate(680 mg, 46% 4 steps yield) as white solid. LC-MS: 512.8[M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[[2-(dimethylamino)-4-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-pyridyl]methyl]carbamate(500 mg, 0.980 mmol) in dichloromethane (10 ml) and tetrahydrofuran (10ml) was added manganese(IV) oxide (1695.93 mg, 19.51 mmol) and stirredat 25° C. for 1 h. After completion of reaction, reaction mixture wasfiltered and concentrated under vacuum. The crude, thus obtained waspurified by trituration with 20% ethyl acetate in n-hexane to afford9H-fluoren-9-ylmethylN-[[2-(dimethylamino)-4-[(3-formyl-2-pyridyl)sulfanyl]-3-pyridyl]methyl]carbamate(247.7 mg, 49.74% yield) as white solid. LC-MS: 330.1[M+H]⁺. 1H NMR:(400 MHz, DMSO-d6) δ 2.83 (6H, s), 4.19 (1H, d, J=6.6 Hz), 4.23 (2H, d,J=6.9 Hz), 4.28 (2H, d, J=3.9 Hz), 6.92 (1H, d, J=5.0 Hz), 7.30 (2H, t,J=7.1 Hz), 7.36-7.48 (3H, m), 7.52-7.59 (1H, m), 7.66 (2H, d, J=7.4 Hz),7.88 (2H, d, J=7.4 Hz), 8.12 (1H, d, J=5.1 Hz), 8.28-8.35 (1H, m), 8.53(1H, dd, J=4.6, 1.6 Hz), 10.19 (1H, s).

Intermediate 133 (9H-Fluoren-9-yl)methyl((2-chloro-4-((3-formylpyridin-2-yl)thio)pyridin-3-yl)methyl)carbamate

To a stirred solution of 2-mercaptonicotinic acid (10 g, 64.45 mmol) inDMSO (40 ml) was added trifluoroacetic acid (0.49 ml, 6.44 mmol) at 0°C. and the reaction mixture was heated at 60° C. for 24 h. Reactionmixture was then cooled to 0° C., DMF (100 ml) and potassium carbonate(8.91 g, 64.45 mmol) were then added and stirred for 30 min at 0° C.Then iodomethane (12.04 ml, 193.34 mmol) was slowly added at 0° C. andthe reaction mixture was stirred at 25° C. for 16 h.

The reaction mixture was then cooled to 0° C., a solution of acetic acid(13 ml) in water (150 ml) was slowly added and the resulting mixturestirred at 25° C. for 6 h. Precipitated white solid was filtered, washedwith water (3×70 ml) followed by hexane (3×30 ml), dried under vacuum toafford methyl2-[(3-methoxycarbonyl-2-pyridyl)disulfanyl]pyridine-3-carboxylate (8.24g, crude) as white solid. LC-MS: 336.6 [M+H]⁺.

To a stirred solution of methyl2-[(3-methoxycarbonyl-2-pyridyl)disulfanyl]pyridine-3-carboxylate (8.2g, 24.38 mmol) in 1,4-dioxane (34 ml) were added triphenyl phosphine(8.95 g, 34.13 mmol) and water (18 ml) successively at 25° C. and heatedat 65° C. for 16 h. Then the reaction mixture was concentrated undervacuum. The residue thus obtained was diluted with EtOH (85 ml) andheated at 75° C. for 15 min. The reaction mixture was then cooled to 25°C. slowly followed to 0° C. by 4 h. The solid was then collected byfiltration and dried under vacuum to afford methyl2-sulfanylpyridine-3-carboxylate (7.54 g, 69.17% yield over 2 steps) asyellow solid. LC-MS: 170.1 [M+H]⁺.

The title compound was then prepared in analogy to Intermediate 63starting from 2-chloro-4-fluoro-pyridine-3-carbaldehyde and methyl2-sulfanylpyridine-3-carboxylate. The title compound was obtained aswhite solid (655 mg). MS ESI (m/z): 502.0 [(M+H)⁺].

1H NMR: (400 MHz, DMSO-d6) δ 4.18 (1H, d, J=6.2 Hz), 4.24 (2H, d, J=6.8Hz), 4.37 (2H, d, J=4.2 Hz), 7.31 (2H, t, J=7.3 Hz), 7.40 (2H, t, J=7.4Hz), 7.45 (1H, dd, J=7.4, 5.0 Hz), 7.50 (1H, d, J=5.0 Hz), 7.67 (3H, d,J=7.3 Hz), 7.88 (2H, d, J=7.4 Hz), 8.35-8.39 (2H, m), 8.52 (1H, d, J=3.3Hz), 10.18 (1H, s).

Intermediate 134 9H-Fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl) sulfanyl]-5-(pyrrolidin-1-yl)phenyl} methyl) carbamate

To a stirred solution ofN-({5-bromo-2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chlorophenyl}methyl)-2-methylpropane-2-sulfinamide(500 mg, 0.867 mmol) in toluene (5 mL) were added pyrrolidine (73.955mg, 1.04 mmol) and sodium tertiary butoxide (224.844 mg, 2.34 mmol) anddegassed in argon atmosphere for 5 min. Then to it were added2-ditertiary butyl phosphino biphenyl (23.272 mg, 0.078 mmol) andPd(dba)₂ (39.861 mg, 0.069 mmol) and heated to 110° C. for 16 h.Reaction mass was filtered through celite pad and the filtrate wasevaporated under reduced pressure to getN-({2-[(3-{[(tert-Butyldimethylsilyl) oxy] methyl} pyridin-2-yl)sulfanyl]-3-chloro-5-(pyrrolidin-1-yl) phenyl}methyl)-2-methylpropane-2-sulfinamide (500 mg, crude) as off whitesolid; which was directly used for next step. LC-MS: 584.3 [M+H]⁺.

To a stirred solution ofN-({2-[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)sulfanyl]-3-chloro-5-(pyrrolidin-1-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide(600 mg, 1.058 mmol) in MeOH (10 mL), was added 4M HCl in dioxan (5 mL)at 0° C. and reaction mixture was stirred at 25° C. for 2 h. Reactionmass was evaporated under reduced pressure to get(2-{[2-(aminomethyl)-6-chloro-4-(pyrrolidin-1-yl) phenyl]sulfanyl}pyridin-3-yl)methanol as HCl salt (350 mg, crude) as off whitesolid which was directly used for next step. LC-MS: 349.8 [M+H]⁺.

To a stirred suspension of(2-{[2-(aminomethyl)-6-chloro-4-(pyrrolidin-1-yl)phenyl]sulfanyl}pyridin-3-yl)methanolHCl salt (1.0 g, 2.865 mmol) in 5% NaHCO₃ (10 mL) was added Fmoc OSU(966 mg, 2.865 mmol) in dioxan (10 mL) at 25° C. and reaction mass wasstirred at the same temperature for 16 h. Then reaction mass was dilutedwith water and extracted with ethyl acetate. The separated organic layerwas washed with brine solution, dried over sodium sulfate and evaporatedunder reduced pressure to get 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyrrolidin-1-yl)phenyl)methyl]carbamate(1.1 g, crude) as off white solid; which was used for next step withoutfurther purification. LC-MS: 571.8 [M+H]⁺.

To a stirred solution of 9H-fluoren-9-ylmethylN-[(3-chloro-2-{[3-(hydroxymethyl)pyridin-2-yl]sulfanyl}-5-(pyrrolidin-1-yl)phenyl)methyl]carbamate(1.1 g, 1.926 mmol) in DCM/THF (1:1, 20 mL) was added MnO₂(2.512 g,28.897 mmol)) and reaction mass was stirred at 25° C. for 2 h. Thereaction mass was filtered through celite pad; filtrate was evaporatedunder reduced pressure. The crude thus obtained was purified bycombi-flash column chromatography (40 g; 40-80% EtOAC/Hexanes) to givean impure mixture which was finally purified by reverse phase prep-HPLCto give 9H-fluoren-9-ylmethylN-({3-chloro-2-[(3-formylpyridin-2-yl)sulfanyl]-5-(pyrrolidin-1-yl)phenyl}methyl)carbamate(150 mg, 10%, 4 steps) as a off white solid. LC-MS: 570.0 [M+H]⁺.

¹H-NMR: (400 MHz, DMSO-d6): δ 1.90-1.95 (4H, m), 3.23 (4H, m), 4.20-4.27(5H, m), 6.51 (1H, s), 6.62 (1H, s) 7.30-7.32 (3H, m), 7.39-7.41 (2H,m), 7.68 (2H, d, J=7.2 Hz), 7.70 (1H, m), 7.90 (2H, d, J=7.12 Hz), 8.31(1H, m), 8.4 (1H, s), 10.21 (1H, s).

Intermediate 1353-[(12S,15S,18S)-15-(4-tert-Butoxycarbonylamino-butyl)-18-(3-tert-butoxycarbonylamino-propyl)-6-bromo-4-chloro-13-methyl-11,14,17-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-12-ylmethyl]-indole-1-carboxylicacid tert-butyl ester

Intermediate 135 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 89

MS (M+H)⁺: expected 1082.37; observed 1082.5

Intermediate 1363-[(12S,15S,18S)-15-(4-tert-Butoxycarbonylamino-butyl)-18-(3-tert-butoxycarbonylamino-propyl)-5-bromo-4-chloro-13-methyl-11,14,17-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-12-ylmethyl]-indole-1-carboxylicacid tert-butyl ester

Intermediate 136 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 100

MS (M+H)⁺: expected 1082.37; observed 1082.5

Intermediate 1373-[(12S,15S,18S)-15-(4-tert-Butoxycarbonylamino-butyl)-18-(3-tert-butoxycarbonylamino-propyl)-23-bromo-4-chloro-13-methyl-11,14,17-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-12-ylmethyl]-indole-1-carboxylicacid tert-butyl ester

Intermediate 137 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 115

MS (M+H)⁺: expected 1082.37; observed 1082.5

Intermediate 1383-[(12S,15S,18S)-15-(4-tert-Butoxycarbonylamino-butyl)-18-(3-tert-butoxycarbonylamino-propyl)-24-bromo-4-chloro-13-methyl-11,14,17-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-12-ylmethyl]-indole-1-carboxylicacid tert-butyl ester

Intermediate 138 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 120

MS (M+H)⁺: expected 1082.37; observed 1082.6

Intermediate 1383-[(12S,15S,18S)-15-(4-tert-Butoxycarbonylamino-butyl)-18-(3-tert-butoxycarbonylamino-propyl)-24-bromo-4-chloro-13-methyl-11,14,17-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-12-ylmethyl]-indole-1-carboxylicacid tert-butyl ester

Intermediate 138 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 120

MS (M+H)⁺: expected 1082.37; observed 1082.6

Intermediate 139(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-6,7,9,10,12,13,15,16-octahydro-12-methyl-13-[(2-methyl-1H-indol-3-yl)methyl]-18-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]pyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecine-8,11,14(5H)-trione

Intermediate 138 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 60

MS (M+H)⁺: expected 1083.3; observed 1084.5

Intermediate 140 1H-indole-1-carboxylic acid,3-[[(7S,10S,13S)-17-bromo-20-chloro-10-[4-[[(1,1-dimethylethoxy)carbonyl]amino]butyl]-7-[3-[[(1,1-dimethylethoxy)carbonyl]amino]propyl]-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-12-methyl-8,11,14-trioxopyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecin-13-yl]methyl]-,1,1-dimethylethyl ester

Intermediate 140 was prepared according to the General Procedure forPeptide Macrocycle Synthesis, but BOC-protecting groups were kept intact(no TFA deprotection) using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 59

MS (M+H)⁺: expected 1083.3; observed 1084.5

Intermediate 141(2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoicacid

The title compound was prepared according to the following scheme:

Step 1: Preparation of benzyl(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-hydroxy-pentanoate(Compound i141b)

To a mixture of(4S)-5-benzyloxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-pentanoicacid (i141a, 1.84 g, 4 mmol) and 4-methylmorpholine (607 mg, 0.66 mL, 6mmol) in dry THF (20 ml) at −10° C. was added dropwise isobutylcarbonochloridate (660 mg, 4.8 mmol). The resulting reaction mixture wasstirred at −10° C. for 2 hours, then poured into a mixture of NaBH₄ (460mg, 12 mmol) and ice (10 g) and stirred for further 30 minutes. Thereaction mixture was diluted with ice-cooled water, and extracted withEA twice. The combined organic phase was dried and concentrated. Theresidue was purified by silica gel column to give compound i1141b (1.34g). MS (M+H⁺): 446.

Step 2: Preparation of benzyl(2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoate(Compound i141c)

To a mixture of benzyl(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-hydroxy-pentanoate(compound i141b, 1.34 g, 3 mmol) and imidazole (610 mg, 9 mmol) in DCM(15 ml) was added a solution of tert-butylchlorodimethylsilane (540 mg,3.6 mmol) in DCM (5 ml). The reaction mixture was stirred at roomtemperature for 3 hours, and then concentrated. The residue wasdissolved in PE/EA=5/1, and washed with water. The organic phase wasseparated and concentrated. The residue was purified by silica gelcolumn to give compound i141c (1.3 g). MS (M+H⁺): 560.

Step 3: Preparation of(2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoicacid (Intermediate i141)

To a solution of benzyl(2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoate(compound i141c, 1.3 g, 2.3 mmol) in EtOH/i-PrOH/H₂O=89/5/6 (15 ml) wasadded Lindlar catalyst (Aldrich, 390 mg). The reaction mixture washeated at 40° C. under a H₂ balloon for 5 hours. After cooled to roomtemperature, the reaction mixture was filtered. The filtrate was treatedwith aq. HCl solution (1 N) to pH=6 and concentrated. The residue wastaken up in EA, washed with brine, dried, and concentrated to give crudecompound i141 (1.0 g). MS (M+H⁺): 470.

General Procedure for Peptide Macrocycle Synthesis

1. Solid Phase Peptide Synthesis

The tripeptide sequence was synthesized manually via state-of-the-artsolid phase synthesis protocols (Fmoc-chemistry) as referenced by e.g.:Kates and Albericio, Eds., “Solid Phase Synthesis: A practical guide”,Marcel Decker, New York, Basel, 2000.

As a solid support 2-Chlor-tritylchloride resin (1.6 meq/g, 100-200mesh) was used. This resin was loaded with 0.6 eq of amino acid and 8 eqDIPEA in dry DCM overnight at RT. After extensive washing with DMF andDCM, the Fmoc-group was cleaved off with a mixture of 50% Piperidine inDCM/DMF (1:1) in DMF (freshly prepared) for 30 min at RT. After washingwith DMF, DCM and MeOH the resin was dried under vacuum at RT overnight.The resin loading was determined via weight increase.

The second amino acid was coupled with 4 eq Mukaiyama-Reagent ascoupling reagent, 6 eq DIPEA in DMF/DCM (1:1) overnight at RT. The resinwas extensively washed with DMF and DCM and the coupling rate wascontrolled by a test-cleavage.

The Fmoc-group from the dipeptide was cleaved with a mixture of 50%Piperidine (25%)/DCM (25%) in DMF for maximally 5 min followed bywashings with DMF and DCM. The cleavage rates were again controlled bytest-cleavage.

The third amino acid was coupled using an excess of 4 eq using 4 eq HATUas coupling reagent and 6 eq DIPEA. Complete couplings were accomplishedat RT for 2-4 hours with the coupling rate again controlled by atest-cleavage.

The Fmoc-group from the tripeptide was cleaved with a mixture of 20%Piperidine in DMF for 2×15-20 min at RT followed by washings with DMFand DCM (test-cleavage).

On-Bead N-Methylation:

In case the N-methylated amino acids were not commercially availablethey were alkylated on the solid phase as follows:

-   -   Resin was swollen in THF (ca. 10 ml/g resin). 12 eq DIPEA were        added and the reaction mixture was shaken at RT for 15 min. 3 eq        2-nitrobenzene-1-1sulfonylchloride were added and the resin was        shaken at RT overnight. Resin was then drained, washed with DCM        and DMF. The coupling rate was controlled via a test-cleavage.    -   For the second step the Resin was suspended in DMF, 12 eq MTBD        (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) were added and        the reaction mixture was shaken at RT for 10 min. Then 3 eq        Methyl-4-nitrobenzenesulfonate was added and the slurry was        shaked at RT. After 30 min. The resin was drained and washed        with DMF and DCM. The coupling rate was controlled via a        test-cleavage.    -   For removal of the 2-nitrobenzene-1-1sulfonamide protecting        group, the resin was suspended in DMF, 12 eq DBU were added, the        slurry shaken for 5 min, then 12 eq mercaptoethanol was added        and the reaction mixture was shaken at RT for 1 h. The resin was        drained and washed with DMF and DCM. The deprotection rate was        controlled via a test-cleavage.

2. Reductive Amination:

Resin with tripeptide was washed with DCM, the correspondingIntermediate dissolved in a mixture of NMP/TMOF/AcOH (49.7/49.7/0.6) andthe solution was added to the resin. The mixture was shaken at RT for 30min up to 3 h, then 10 eq NaCNBH₃ were added and the reaction mixturewas shaken at RT overnight. Finally, the resin was washed with DMF, DCM,MeOH/DCM (1:1) and DMF.

The Fmoc-group on the third amino acid was cleaved with a mixture of 20%Piperidine in DMF for 2×15-20 min at RT followed by washings with DMFand DCM (test-cleavage).

3. Cleavage:

A cleavage-cocktail of 20% HFIP in DCM was added to the resin and themixture was stirred for 2 h at RT. The resin was filtered off and thesolution was evaporated to dryness. The residue was dissolved inwater/acetonitrile and lyophilized.

4. Cyclisation:

The obtained crude linear compound was cyclized by dissolving the powderin DMF. 1.2 eq HATU and 5 eq DIPEA were added and the reaction mixturestirred at RT. Progress of the reaction was monitored by HPLC. Aftercompletion, the solvent was evaporated, the resulting residue taken upin water/acetonitrile (1:1) and lyophilized.

5. Purification:

Peptide macrocycles were purified using reversed phase high-performanceliquid chromatography (RP-HPLC) using a Reprospher 100 C18-TDE column(250×20 mm, 5 um particle size) as a stationary phase andwater/acetonitrile as eluent (Gradient 40-100% MeCN over 60 min).Fractions were collected and analyzed by LC/MS. Pure product sampleswere combined and lyophilized. Product identification was obtained viamass spectrometry.

6. Global Deprotection:

Final BOC-deprotection was achieved by 50% TFA (DCM) treatment for 2 hat RT. The reaction solution was concentrated down and the residuefreeze-dried to yield the deprotected product as TFA salt. All peptideswere obtained as white powders with a purity >90%.

General Procedure for Suzuki Coupling of Boronic Acid Derivatives toPeptide Macrocycle Intermediates

In a reaction tube to a solution of protected bromide MacrocycleIntermediate (46.1 μmol, Eq: 1) in Dioxane (1.2 ml) was added at 22° C.water (400 μl) followed by sodium carbonate (115 μmol, Eq: 2.5) and theBoronic Acid Derivative (92.3 μmol, Eq: 2). The mixture was degassed bybubbling argon into the reaction mixture for 5 minutes. Then was addedtetrakis(triphenylphosphine)palladium (0) (2.31 μmol, Eq: 0.05), thetube was inerted, sealed and the reaction mixture was stirred at 80° C.for 2 h or till complete conversion.

The mixture was evaporated, treated with water (2 ml) and extracted withDCM (2×2 ml). The organic layers were dried, evaporated to dryness,purified by preparative HPLC and lyophlized to give the pure product asa lyophilized solid.

Boc-Deprotection

To a solution of lyophilized solid (15 μmol) in DCM (1.6 ml) was addedat 22° C. TFA (0.4 ml) (5.22 mmol=ca. 350 eq) and stirred for 2 h togive complete conversion.

After total 2 h the mixture was evaporated, the residue was dissolved inACN and H₂O (containing 0.1% TFA), allowed to stand for 4 h at 22° C.and dried frozen/lyophilized to give the peptide macrocycle as whitelyoph solid.

Example 1(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 1 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 4

MS (M+H)⁺: expected 696.3; observed 670.3

Example 2(12S,15S,18S)-15,18-Bis-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 2 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Orn(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 4

MS (M+H)⁺: expected 655.3; observed 656.3

Example 3(12S,15S,18S)-15-(4-Amino-butyl)-12-(1H-indol-3-ylmethyl)-13-methyl-18-piperidin-4-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 3 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. 2-(Fmoc-amino)-2-(1-Boc-4-piperidyl)acetic acid.

Tether: Intermediate 4

MS (M+H)⁺: expected 695.4; observed 696.4

Example 4(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 4 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 3

MS (M+H)⁺: expected 703.3; observed 704.3

Example 5N-[(11S,14S,17S)-14-(4-Amino-butyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-ylmethyl]-guanidine

Example 5 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Agp(Boc2)-OH.

Tether: Intermediate 4

MS (M+H)⁺: expected 683.3; observed 684.3

Example 6(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 6 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 2

MS (M+H)⁺: expected 703.3; observed 704.3

Example 7(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 7 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 5

MS (M+H)⁺: expected 699.4; observed 700.4

Example 8(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 8 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 6

MS (M+H)⁺: expected 683.4; observed 684.4

Example 9(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-5,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 9 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 7

MS (M+H)⁺: expected 683.4; observed 684.4

Example 10(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 10 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 8

MS (M+H)⁺: expected 683.4; observed 684.4

Example 11(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 11 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 1

MS (M+H)⁺: expected 703.3; observed 705.2

Example 12(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 12 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 9

MS (M+H)⁺: expected 737.3; observed 738.1

Example 13(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-5-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 13 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 10

MS (M+H)⁺: expected 737.3; observed 738.4

Example 14(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 14 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 11

MS (M+H)⁺: expected 737.3; observed 738.3

Example 15(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(6-chloro-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 15 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-6-Cl-Trp-OH, followed by on-bead N-methylation of the        Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 4

MS (M+H)⁺: expected 703.3; observed 704.3

Example 16(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

N-Methylation at Indole nitrogen occurred upon N-alkylation of activatedTrp alpha-N. Example 16 was isolated from crude mixture of Example 15using standard HPLC purification conditions.

MS (M+H)⁺: expected 717.3; observed 718.3

Example 17(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-methyl-12-(1-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 17 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(NMe)-OH, followed by on-bead N-methylation of the        Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 3

MS (M+H)⁺: expected 717.3; observed 718.3

Example 18(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(6-chloro-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 18 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-6-Cl-Trp-OH, followed by on-bead N-methylation of the        Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 3

MS (M+H)⁺: expected 737.3; observed 738.3

Example 19(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-1,14,17-trione

N-Methylation at Indole nitrogen occurred upon N-alkylation of activatedTrp alpha-N. Example 19 was isolated from crude mixture of Example 18using standard HPLC purification conditions.

MS (M+H)⁺: expected 751.3; observed 752.3

Example 20(9S,12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-9,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 20 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 12

MS (M+H)⁺: expected 717.3; observed 718.3

Example 21(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6,7-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 21 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 14

MS (M+H)⁺: expected 737.3; observed 738.3

Example 22(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-7-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 22 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 15

MS (M+H)⁺: expected 703.3; observed 704.3

Example 23(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,7-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 23 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 13

MS (M+H)⁺: expected 737.3; observed 738.4

Example 24(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-7-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 24 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 16

MS (M+H)⁺: expected 771.3; observed 772.2

Example 25(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 25 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 21

MS (M+H)⁺: expected 771.2; observed 772.3

Example 26(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-7-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 26 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 22

MS (M+H)⁺: expected 721.3; observed 722.3

Example 27(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 27 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 26

MS (M+H)⁺: expected 755.3; observed 756.3

Example 28(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 28 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 54

MS (M+H)⁺: expected 704.3; observed 705.4

Example 29(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,7-difluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 29 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 17

MS (M+H)⁺: expected 705.3; observed 706.3

Example 30(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 30 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 19

MS (M+H)⁺: expected 687.3; observed 688.3

Example 31(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 31 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 20

MS (M+H)⁺: expected 771.3; observed 772.3

Example 32(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 32 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 4

MS (M+H)⁺: expected 683.4; observed 684.4

Example 33(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 33 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 24

MS (M+H)⁺: expected 704.3; observed 705.3

Example 34(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 34 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 25

MS (M+H)⁺: expected 704.3; observed 705.4

Example 35(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-22-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 35 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 53

MS (M+H)⁺: expected 687.3; observed 688.3

Example 36(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 36 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 23

MS (M+H)⁺: expected 738.3; observed 739.2

Example 37(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,23-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 37 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 29

MS (M+H)⁺: expected 738.3; observed 739.2

Example 38(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 38 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 30

MS (M+H)⁺: expected 738.3; observed 739.3

Example 39(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 39 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 772.3; observed 9773.2

Example 40(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-difluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 40 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 32

MS (M+H)⁺: expected 706.3; observed 707.3

Example 41(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-6,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 41 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 36

MS (M+H)⁺: expected 717.3; observed 718.3

Example 42(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 42 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 37

MS (M+H)⁺: expected 737.3; observed 738.3

Example 43(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-ethyl-12-(1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 43 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 3

MS (M+H)⁺: expected 717.3; observed 718.3

Example 44(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-6-methoxy-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 44 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 5

MS (M+H)⁺: expected 729.4; observed 730.4

Example 45(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-13-ethyl-12-(1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 45 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 1

MS (M+H)⁺: expected 717.3; observed 718.3

Example 46(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-4-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 46 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 6

MS (M+H)⁺: expected 697.4; observed 698.4

Example 47(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 47 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 35

MS (M+H)⁺: expected 687.3; observed 688.3

Example 48(12S,15S,18S)-15-(4-Amino-butyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-18-(4-methylamino-butyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 48 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-Lys(Me,BOC)—OH.

Tether: Intermediate 1

MS (M+H)⁺: expected 731.4; observed 732.4

Example 49(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 49 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 33

MS (M+H)⁺: expected 733.3; observed 734.3

Example 50(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 50 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 34

MS (M+H)⁺: expected 713.4; observed 714.4

Example 51(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16,25-dimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 51 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 40

MS (M+H)⁺: expected 684.4; observed 685.3

Example 52(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 52 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 28

MS (M+H)⁺: expected 722.3; observed 723.3

Example 53(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 53 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 23

MS (M+H)⁺: expected 738.3; observed 739.3

Example 54(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 54 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 27

MS (M+H)⁺: expected 722.3; observed 723.3

Example 55(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 55 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 38

MS (M+H)⁺: expected 717.3; observed 718.3

Example 56(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 56 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 39

MS (M+H)⁺: expected 687.3; observed 688.3

Example 57(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 57 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 3

MS (M+H)⁺: expected 717.3; observed 718.3

Example 58(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,13-dimethyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 58 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 6

MS (M+H)⁺: expected 697.7; observed 698.4

Example 59(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 59 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 37

MS (M+H)⁺: expected 751.3; observed 752.3

Example 60(9S,12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-9,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 60 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 41

MS (M+H)⁺: expected 717.3; observed 718.3

Example 61(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-23-methoxy-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 61 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 43

MS (M+H)⁺: expected 700.3; observed 701.6

Example 62(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 62 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 45

MS (M+H)⁺: expected 772.3; observed 773.3

Example 63(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 63 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 46

MS (M+H)⁺: expected 670.3; observed 671.3

Example 64(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 64 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 42

MS (M+H)⁺: expected 721.3; observed 772.3

Example 65(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-fluoro-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 65 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 44

MS (M+H)⁺: expected 701.3; observed 702.6

Example 66(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-ethyl-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 66 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 49

MS (M+H)⁺: expected 997.4; observed 998.4

Example 67(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 67 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H)⁺: expected 738.3; observed 739.3

Example 68(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 68 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 48

MS (M+H)⁺: expected 772.3; observed 773.3

Example 69(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 69 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 50

MS (M+H)⁺: expected 745.4; observed 746.4

Example 70(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-tert-butyl-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 70 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 51

MS (M+H)⁺: expected 725.4; observed 726.4

Example 71(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-methoxy-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione

Example 71 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 5

MS (M+H)⁺: expected 713.9; observed 714.4

Example 72(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-isopropyl-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 72 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 52

MS (M+H)⁺: expected 711.4; observed 712.4

Example 73(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 73 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 27

MS (M+H)⁺: expected 722.3; observed 723.3

Example 74(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 74 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 45

MS (M+H)⁺: expected 786.6; observed 787.3

Example 75(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 75 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 786.3; observed 787.3

Example 76(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 76 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-2-Methyl-L-Trp-OH, followed by on-bead N-methylation of        the Trp alpha-N,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H)⁺: expected 752.3; observed 753.3

Example 77(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 77 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 45

MS (M+H)⁺: expected 786.3; observed 787.4

Example 78(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-16-ethyl-7-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 78 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 30

MS (M+H)⁺: expected 752.3; observed 753.3

Example 79(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 79 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 786.3; observed 787.3

Example 80(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 80 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (Intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H)⁺: expected 752.3; observed 753.3

Example 81(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 81 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H)⁺: expected 724.2; observed 725.2

Example 82(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 82 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 30

MS (M+H)⁺: expected 724.2; observed 725.2

Example 83(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 83 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 45

MS (M+H⁺): expected 796.3; observed 787.3

Example 84(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-16-ethyl-17-(1H-indol-3-ylmethyl)-25-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 84 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NEt-L-Trp(BOC)—OH (intermediate 55),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 56

MS (M+H⁺): expected 776.8; observed 777.3

Example 85(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-(3-methyl-3H-imidazol-4-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 85 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(3-methyl-3H-imidazol-4-yl)-propionic        acid.

Tether: Intermediate 45

MS (M+H⁺): expected 809.3; observed 810.3

Example 86(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-pyridin-3-ylmethyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 86 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-pyridin-3-yl-propionic        acid.

Tether: Intermediate 45

MS (M+H⁺): expected 806.3; observed 807.3

Example 87(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-23-phenyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 87 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 57

MS (M+H⁺): expected 806.3; observed 807.3

Example 88(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 88 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 58

MS (M+H⁺): expected 816.8; observed 817.5

Example 89(11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-23-bromo-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 89 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 59

MS (M+H⁺): expected 783.2; observed 784.2

Example 90(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-bromo-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 90 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 60

MS (M+H⁺): expected 783.2; observed 784.2

Example 91(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-23,25-bis-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 91 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 61

MS (M+H⁺): expected 805.9; observed 807.3

Example 92(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-morpholin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 92 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 62

MS (M+H⁺): expected 789.4; observed 790.3

Example 93(14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 93 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gly-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 682.7; observed 683.2

Example 94(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11,16-dimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 94 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Ala-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 695.7; observed 696.2

Example 95(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11-isopropyl-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 95 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Leu-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 723.7; observed 724.3

Example 96(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-hydroxymethyl-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 96 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Ser(tBu)-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 711.7; observed 712.2

Example 97(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 97 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 63

MS (M+H⁺): expected 773.3; observed 774.3

Example 98(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 98 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 64

MS (M+H⁺): expected 773.3; observed 774.3

Example 99(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 99 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 65

MS (M+H⁺): expected 781.4; observed 782.4

Example 100(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 100 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 66

MS (M+H⁺): expected 781.4; observed 782.4

Example 101(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11-isobutyl-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 101 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Leu-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 737.8; observed 738.3

Example 102(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(2-methoxy-pyridin-4-yl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 102 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 67

MS (M+H⁺): expected 811.4; observed 812.4

Example 1033-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide

Example 103 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 752.7; observed 753.3

Example 104(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 104 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 68

MS (M+H⁺): expected 738.4; observed 739.3 [(M+H)⁺]

Example 105(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 105 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 65

MS (M+H⁺): expected 795.4; observed 796.4

Example 106(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-((S)-1-hydroxy-ethyl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 106 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Thr(tBu)-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 725.7; observed 726.3

Example 107(14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11,11,16-trimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 107 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-Aib-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 709.7; observed 710.3

Example 108(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-naphthalen-2-ylmethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 108 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-2-Nal-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 821.8; observed 822.3

Example 109(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 109 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 70

MS (M+H⁺): expected 796.4; observed 797.3

Example 110(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 110 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 71

MS (M+H⁺): expected 739.3; observed 740.3 [(M+H)⁺]

Example 111(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 111 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 72

MS (M+H⁺): expected 772.3; observed 773.3 [(M+H)⁺]

Example 112(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 112 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 73

MS (M+H⁺): expected 772.3; observed 773.3 [(M+H)⁺]

Example 113(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 113 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 74

MS (M+H⁺): expected 704.3; observed 705.3 [(M+H)⁺]

Example 114(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-naphthalen-1-ylmethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 114 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-1-Nal-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 821.8; observed 822.3

Example 115(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 115 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 75

MS (M+H⁺): expected 821.8; observed 822.3

Example 116{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecin-18-yl}boronicacid

Example 116 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 76

MS (M+H⁺): expected 748.1; observed 749.4

Example 117(12S,15S,18S)-15-(3-Amino-propyl)-18-biphenyl-4-ylmethyl-12-(1H-indol-3-ylmethyl)-19-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 117 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Orn(BOC)—OH,    -   3. Fmoc-L-NMe-Bip(BOC)—OH.

Tether: Intermediate 4

MS (M+H)⁺: expected 765.35; observed 765.42

Example 118(11S,14S,17S)-14-(4-Amino-butyl)-11-(2-amino-ethoxymethyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 118 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3.        (S)-3-(2-tert-Butoxycarbonylamino-ethoxy)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic        acid Tether: Intermediate 31

MS (M+H)⁺: expected 789.29; observed 789.34

Example 119(11S,14S,17S)-11,14-Bis-(2-amino-ethoxymethyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 119 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-Trp(BOC)—OH,    -   2.        (S)-3-(2-tert-Butoxycarbonylamino-ethoxy)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic        acid    -   3.        (S)-3-(2-tert-Butoxycarbonylamino-ethoxy)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic        acid Tether: Intermediate 31

MS (M+H)⁺: expected 791.26; observed 791.27

Example 120(11S,14S,17S)-14-(2-Amino-ethoxymethyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 120 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   Fmoc-L-NMe-Trp(BOC)—OH,    -   (S)-3-(2-tert-Butoxycarbonylamino-ethoxy)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic        acid    -   Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 775.27; observed 775.22

Example 1213-[(11S,14S,17S)-14-(4-Amino-butyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide

Example 121 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 30

MS (M+H⁺): expected 752.7; observed 753.3

Example 122(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 122 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 77.Macrocyclization: 2.4 eq HATU, 10 eq DIPEA, in DMF at rt 4 h.Deprotection: DCM/TFA 2:1. The title compound was obtained as lightyellow powder (6 mg). MS ESI (m/z): 773.3 [(M+H)⁺].

Example 123(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 123 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 78.Macrocyclization: 2.4 eq HATU, 10 eq DIPEA, in DMF at rt 2 h.Deprotection: DCM/TFA 2:1. The title compound was obtained as red solid(12 mg). MS ESI (m/z): 773.3 [(M+H)⁺].

Example 124(11R,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 124 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-D-Orn(BOC)—OH.

Tether: Intermediate 79

MS (M+H)⁺: expected 767.32; observed 767.33

Example 125(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 125 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 79

MS (M+H)⁺: expected 767.32; observed 767.32

Example 126(11R,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 126 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-D-Orn(BOC)—OH.

Tether: Intermediate 79

MS (M+H)⁺: expected 781.33; observed 781.34

Example 1272-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-acetamide

Example 127 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Asn(Trt)-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 738.7; observed 739.2

Example 128(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 128 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 80

MS (M+H)⁺: expected 814.36; observed 814.37

Example 129(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 129 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 81

MS (M+H⁺): expected 780.4; observed 781.3

Example 130(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrrolidin-1-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 130 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 134

MS (M+H⁺): expected 773.4; observed 774.4

Example 131(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(5-fluoro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 131 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-5-F-Trp-OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 791.28; observed 791.44

Example 132(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-quinolin-2-ylmethyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 132 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-β-(2-quinolyl)-Ala-OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 785.29; observed 785.43

Example 133(12S,15S,18S)-15,18-Bis-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 133 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Orn(BOC)—OH.    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H)⁺: expected 724.25; observed 724.20

Example 1343-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(2-methoxy-pyridin-4-yl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23exaen-11-yl]-propionamide

Example 134 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 67

MS (M+H⁺): expected 825.4; observed 826.3

Example 135(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(5-chloro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 135 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-5-Cl-Trp-OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 807.25; observed 807.39

Example 136(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(2,3-dihydro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione

Example 136 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-DHT(BOC)—OH (wherein DHT is dihydrotryptophan),    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 31

MS (M+H)⁺: expected 775.30; observed 775.42

Example 1373-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-morpholin-4-yl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide

Example 137 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 62

MS (M+H⁺): expected 803.4; observed 804.3

Example 138(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,6-dihydro-2H-pyran-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 138 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 83

MS (M+H⁺): expected 786.4; observed 787.4

Example 139{3-[(11S,14S,17S)-14-(4-Amino-butyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propyarbamicacid benzyl ester

Example 139 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(CBZ)-OH.

Tether: Intermediate 30

MS (M+H⁺): expected 872.9; observed 873.3

Example 140(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 140 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 135    -   Boronic Acid Derivative: Phenylboronic acid

MS (M+H)⁺: expected 780.34; observed 780.5

Example 141(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-6-(2-chloro-phenyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 141 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 135    -   Boronic Acid Derivative: (2-chlorophenyl)boronic acid

MS (M+H)⁺: expected 814.30; observed 814.5

Example 142(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-pyridin-3-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 142 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 135    -   Boronic Acid Derivative: Pyridin-3-yl boronic acid

MS (M+H)⁺: expected 781.33; observed 781.6

Example 143(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-pyridin-4-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 143 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 135    -   Boronic Acid Derivative: Pyridin-4-yl boronic acid

MS (M+H)⁺: expected 781.33; observed 781.5

Example 144(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-(1-methyl-1H-pyrazol-3-yl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 144 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 135    -   Boronic Acid Derivative:        1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

MS (M+H)⁺: expected 783.34; observed 784.4

Example 1453-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-methyl-pyridin-4-yl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-1-yl]-propionamide

Example 145 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 69

MS (M+H⁺): expected 809.4; observed 810.3

Example 146(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrazin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 146 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 84

MS (M+H⁺): expected 782.4; observed 783.3

Example 147(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-morpholin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 147 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 85

MS (M+H⁺): expected 789.4; observed 790.4

Example 148(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridazin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 148 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 86

MS (M+H⁺): expected 782.4; observed 783.3

Example 14911-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 149 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 87

MS (M+H⁺): expected 780.4; observed 781.5

Example 150(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15-18-trione

Example 150 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 88

MS (M+H⁺): expected 781.4; observed 782.6

Example 151(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 151 was prepared by BOC-deprotection of intermediate 135.

MS (M+H)⁺: expected 782.22; observed 782.3

Example 152(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-1,4-dichloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 90.Macrocyclization: 1.4 eq HATU, 10 eq DIPEA, in DCM at rt over night.Deprotection: DCM/TFA 1:1 at 40° C. The title compound was obtained asblue powder (13 mg). MS ESI (m/z): 739.3 [(M+H)⁺].

Example 153(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-3-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 91 usingNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 2.4 eqHATU, 10 eq DIPEA, in DCM at rt over night. Deprotection: DCM/TFA 1:1 at30° C. The title compound was obtained as off white powder (6 mg). MSESI (m/z): 705.3 [(M+H)⁺].

Example 154(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 154 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 135    -   Boronic Acid Derivative:        1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole

MS (M+H)⁺: expected 784.34; observed 784.4

Example 1553-[(11S,14S,17S)-14-(4-Amino-butyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-25-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide

Example 155 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(TRT)-OH.

Tether: Intermediate 80

MS (M+H)⁺: expected 828.34; observed 828.6

Example 156(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-12-methyl-18-(trifluoromethyl)-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 92 usingNMP/MEOH/AcOH 1:1:0.01 as solvent mixture. Macrocyclization: 2.4 eqHATU, 10 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 1:1 at 30° C.The title compound was obtained as white solid (3 mg). MS ESI (m/z):773.3 [(M+H)⁺].

Example 157(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 93 usingDMF/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 1:1, thenconcentrating in vacuo, addition of water and stirring over night. Thetitle compound was obtained as orange solid (31 mg). MS ESI (m/z): 706.4[(M+H)⁺].

Example 158(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-1-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1 eq Intermediate 94 usingNMP/MeOH/AcOH 1:1:0.01 as solvent mixture. Macrocyclization: 2.4 eqHATU, 10 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 1:1 at 30° C.The title compound was obtained as yellow solid (9 mg). MS ESI (m/z):705.3 [(M+H)⁺].

Example 159(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-chloro-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 95 usingNMP/MeOH/AcOH 1:1:0.01 as solvent mixture. Macrocyclization: 2.4 eqHATU, 10 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 1:1 at 30° C.The title compound was obtained as light yellow solid (4 mg). MS ESI(m/z): 706.5 [(M+H)⁺].

Example 1603-[(11S,14S,17S)-14-(3-Amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide

Example 160 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 47

MS (M+H⁺): expected 738.7; observed 739.7

Example 1613-[(11S,14S,17S)-11-(3-Amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-25-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-14-yl]-propionamide

Example 161 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

Amino acids:

-   -   1. Fmoc-L-NMe-Trp(BOC)—OH,    -   2. Fmoc-L-Gln(TRT)-OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 80

MS (M+H)⁺: expected 814.33; observed 814.4

Example 162(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-morpholin-4-yl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 162 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 96

MS (M+H⁺): expected 867.6; observed 868.5

Example 163 (RO7188308-001-001)3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-pyridin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide

Example 163 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 88

MS (M+H⁺): expected 795.4; observed 796.6

Example 164(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-chloro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 164 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 97

MS (M+H⁺): expected 815.8; observed 816.6

Example 165(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 165 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 98

MS (M+H⁺): expected 797.4; observed 798.3

Example 166(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(6-dimethylamino-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 166 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 99

MS (M+H⁺): expected 824.5; observed 825.5

Example 167(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(2-methylpyridin-4-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 95 usingNMP/MeOH/AcOH 1:1:0.01 as solvent mixture. Macrocyclization: 2.4 eqHATU, 10 eq DIPEA, in DCM at rt 1 h. Suzuki in analogy to Example 189using (2-methylpyridin-4-yl)boronic acid. Deprotection: DCM/TFA 1:1,concentration in vacuo, then stirring in acetonitrilewater. The titlecompound was obtained as brown solid (12 mg). MS ESI (m/z): 763.5[(M+H)⁺].

Example 168(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 168 was prepared by BOC-deprotection of intermediate 136.

MS (M+H)⁺: expected 782.22; observed 782.5

Example 1693-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-23-(3,5-dimethyl-isoxazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-1-yl]-propionamide

Example 169 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 101

MS (M+H⁺): expected 813.4; observed 814.3

Example 170(11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 170 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 69

MS (M+H⁺): expected 809.5; observed 810.4

Example 171(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-methoxy-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 171 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 67

MS (M+H⁺): expected 825.4; observed 826.4

Example 172(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 172 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 102

MS (M+H⁺): expected 858.5; observed 859.3

Example 173(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(5-methanesulfonyl-pyridin-3-yl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 173 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 103

MS (M+H⁺): expected 859.5; observed 860.3

Example 174(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(3-amino-pyrrolidin-1-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 174 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 82

MS (M+H⁺): expected 788.4; observed 789.4

Example 175(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,5-dimethyl-1H-pyrazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 175 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 104

MS (M+H⁺): expected 798.4; observed 799.4

Example 176(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-5-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 176 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 136    -   Boronic Acid Derivative: Phenylboronic acid

MS (M+H)⁺: expected 780.34; observed 780.5

Example 177(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 177 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 105

MS (M+H⁺): expected 799.4; observed 800.6

Example 178(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(6-methylpyridin-3-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 95 usingNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Suzuki in analogy to Example 189using (6-methylpyridin-3-yl)boronic acid. Deprotection: DCM/TFA 1:1,concentrated in vacuo, then stirring in acetonitrile/water. The titlecompound was obtained as orange solid (9 mg). MS ESI (m/z): 763.6[(M+H)⁺].

Example 179(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-3-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 106 inNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 1:1, thenconcentrating in vacuo and stirring with acetonitrile/water 1:1. Thetitle compound was obtained as light yellow foam (46 mg). MS ESI (m/z):705.5 [(M+H)⁺].

Example 180[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-ylmethyl]-urea

Example 180 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-ureido-propionic        acid.

Tether: Intermediate 47

MS (M+H⁺): expected 753.7; observed 754.2

Example 181(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 181 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 66

MS (M+H⁺): expected 795.4; observed 796.4

Example 182(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-chloro-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 182 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 97

MS (M+H⁺): expected 829.9; observed 830.3

Example 183(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-fluoro-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 183 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 105

MS (M+H⁺): expected 813.4; observed 814.4

Example 1843-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide

Example 184 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 87

MS (M+H⁺): expected 794.4; observed 795.6

Example 185(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-23-carbonitrile

Example 185 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 107

MS (M+H⁺): expected 729.3; observed 730.4

Example 186(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,5-dimethyl-isoxazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 186 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 101

MS (M+H⁺): expected 799.4; observed 800.3

Example 187(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 187 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 108

MS (M+H⁺): expected 801.4; observed 802.4

Example 188(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(3-benzyloxy-prop-1-ynyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 188 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 109

MS (M+H⁺): expected 848.5; observed 849.4

Example 189(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-phenyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 90 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h.

In a pressure tube to a solution of tert-butyl3-(((8S,11S,14S)-11-(4-((tert-butoxycarbonyl)amino)butyl)-14-(3-((tert-butoxycarbonyl)amino)propyl)-1,4-dichloro-9-methyl-7,10,13-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecin-8-yl)methyl)-1H-indole-1-carboxylate(0.025 g, 24 μmol, Eq: 1) and phenylboronic acid pinacol ester (6.38 mg,31.2 μmol, Eq: 1.3) in dioxane (192 μl) was added 2M aqueous sodiumcarbonate (48.1 μl). The mixture was sparged with argon for 2 minuteswhile sonicating the vessel in an ultra sonic bath. Then Pd(Ph₃P)₄ (5.56mg, 4.81 μmol, Eq: 0.2) was added, sparging continued for 1 minute, thevessel sealed and the reaction mixture heated to 80° C. for 1.5 hours,then to 100° C. over night. The reaction mixture was diluted with ethylacetate, 1M aqueous Na₂CO₃ solution and brine. The mixture was extractedethyl acetate and the organic layers were washed with brine. Thecombined organic layers were dried with sodium sulfate, filtered andconcentrated in vacuo. The obtained material was directly used withoutfurther purification in the deprotection step.

Deprotection: DCM/TFA 2:1, then concentrating in vacuo at roomtemperature and stirring in acetonitrile/water 1:1. The obtainedsolution was directly purified by preparative reversed phase HPLC(Column: Phenomenex Gemini-NX 5u 110A, 1:100 mm, dia: 30 mm) using watercontaining 0.1% TFA/acetonitrile as eluent. The title compound wasobtained as light brown powder (17 mg). MS ESI (m/z): 781.4 [(M+H)⁺].

Example 190(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 190 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 110

MS (M+H⁺): expected 781.4; observed 782.5

Example 191(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 191 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 111

MS (M+H⁺): expected 781.4; observed 781.3

Example 192(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-9-methyl-2-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 0.9 eq Intermediate 112 inNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 1:1. The titlecompound was obtained as white powder (16 mg). MS ESI (m/z): 756.6[(M+H)⁺].

Example 193(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-9-methyl-4-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.3 eq Intermediate 113 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 5 eq DIPEA, in DMF at rt 3 h. Deprotection: DCM/TFA 2:1,concentration in vacuo, then stirring in water. The title compound wasobtained as brown foam (87 mg). MS ESI (m/z): 756.5 [(M+H)⁺].

Example 194(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(pyridin-3-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.3 eq Intermediate 90 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Suzuki in analogy to Example 189using 3-pyridineboronic acid pinacol ester. Deprotection: DCM/TFA 2:1,concentrating under vacuo, stirring with water. The title compound wasobtained as white foam (29 mg). MS ESI (m/z): 782.6 [(M+H)⁺].

Example 195(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(pyridin-4-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.3 eq Intermediate 90 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Suzuki in analogy to Example 189using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.Deprotection: DCM/TFA 2:1, concentrating in vacuo, stirring in water.The title compound was obtained as white foam (23 mg). MS ESI (m/z):782.5 [(M+H)⁺].

Example 196(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-1-(2-methoxypyridin-4-yl)-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.3 eq Intermediate 90 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Suzuki in analogy to Example 189using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.Deprotection: DCM/TFA 2:1, concentrating in vacuo, stirring in water.The title compound was obtained as white foam (33 mg). MS ESI (m/z):812.3 [(M+H)⁺].

Example 197(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-bromo-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 114 usingNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Deprotection: DCM/TFA 2:1,concentrating in vacuo, stirring in water. The title compound wasobtained as white powder (11 mg). MS ESI (m/z): 752.3 [(M+H)⁺].

Example 198(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(2-(trifluoromethyl)pyridin-4-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.3 eq Intermediate 90 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Suzuki in analogy to Example 189using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine.Deprotection: DCM/TFA 2:1, concentration in vacuo, stirring in water.The title compound was obtained as white foam (25 mg). MS ESI (m/z):850.6 [(M+H)⁺].

Example 199(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(5-methanesulfonyl-pyridin-3-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 199 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 103

MS (M+H⁺): expected 873.5; observed 874.5

Example 200(11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 200 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)OH.

Tether: Intermediate 111

MS (M+H⁺): expected 795.4; observed 796.4

Example 201(8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.3 eq Intermediate 90 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h.

In a pressure tube morpholine (8.38 mg, 8.38 μl, 96.1 μmol, Eq: 10) wasadded to tert-butyl3-(((8S,11S,14S)-11-(4-((tert-butoxycarbonyl)amino)butyl)-14-(3-((tert-butoxycarbonyl)amino)propyl)-1,4-dichloro-9-methyl-7,10,13-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecin-8-yl)methyl)-1H-indole-1-carboxylate(0.01 g, 9.61 μmol, Eq: 1) and cesium fluoride (2.92 mg, 19.2 μmol, Eq:2), the tube flushed with argon, sealed and heated to 100° C. overnight. The reaction was dissolved in acetonitrile, treated with waterand the mixture lyophilized. The obtained material was used withoutfurther purification.

Deprotection: DCM/TFA 2:1, concentrating in vacuo, stirring in water.The title compound was obtained as light brown foam (10 mg). MS ESI(m/z): 790.4 [(M+H)⁺].

Example 202(11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 202 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 110

MS (M+H⁺): expected 795.4; observed 796.4

Example 203(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-6,7,9,10,12,13,15,16-octahydro-12-methyl-13-[(2-methyl-1H-indol-3-yl)methyl]-18-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]pyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecine-8,11,14(5H)-trione

Example 203 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 75

MS (M+H⁺): expected 894.5; observed 894.4

Example 204 (RO7192360-001-001)(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-morpholino-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 95 inNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h.

A suspension of tert-butyl3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-18-chloro-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecin-13-yl)methyl)-1H-indole-1-carboxylate(25 mg, 24.8 μmol, Eq: 1) in morpholine (82.8 μl) in a pressure tube washeated to 100° C. and stirred for 2 h. The reaction mixture was dilutedwith acetonitrile/water and lyophilized. tert-Butyl3-(((7S,10S,13S)-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-18-morpholino-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecin-13-yl)methyl)-1H-indole-1-carboxylatewas obtained as white powder and used without purification.

Deprotection: DCM/TFA 1:1, concentration in vacuo, then stirring withwater. The title compound was obtained as white powder (3 mg). MS ESI(m/z): 757.6 [(M+H)⁺]

Example 205(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-(2-methoxypyridin-4-yl)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 95 inNMP/MeOH/AcOH 1:1:0.012 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Suzuki in analogy to Example 189using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.Deprotection: DCM/TFA 1:1, concentration in vacuo, stirring with water.The title compound was obtained as white powder (3 mg). MS ESI (m/z):779.5 [(M+H)⁺].

Example 206(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 206 was prepared by BOC-deprotection of intermediate 137.

MS (M+H)⁺: expected 782.22; observed 782.2

Example 207(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-23-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 207 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 137    -   Boronic Acid Derivative: Phenylboronic acid

MS (M+H)⁺: expected 780.34; observed 780.5

Example 208(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-23-pyridin-3-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 208 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 137    -   Boronic Acid Derivative: Pyridin-3-yl boronic acid

MS (M+H)⁺: expected 781.33; observed 781.3

Example 209(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2,6-difluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3(8),4,6,22,24-hexaene-12,15,18-trione

Example 209 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 139    -   Boronic Acid Derivative: (2,6-difluoropyridin-4-yl)boronic acid

MS (M+H⁺): expected 817.3; observed 818.3

Example 2103-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-N-methyl-propionamide

Example 210 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-methylcarbamoyl-butyric        acid Tether: Intermediate 47

MS (M+H⁺): expected 766.8; observed 767.3

Example 2114-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-23-yl]-benzonitrile

Example 211 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 116

MS (M+H⁺): expected 805.4; observed 806.3

Example 212(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 212 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 117

MS (M+H⁺): expected 795.4; observed 796.4

Example 213(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrimidin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 213 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 118

MS (M+H⁺): expected 782.4; observed 783.4

Example 2144-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-23-yl]-benzenesulfonamide

Example 214 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 119

MS (M+H⁺): expected 859.5; observed 860.7

Example 215(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(2-methylpyridin-4-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 114 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Suzuki in analogy to Example 189using 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.Deprotection: DCM/TFA 1:1, concentration in vacuo, stirring in water.The title compound was obtained as yellow solid (50 mg). MS ESI (m/z):763.4 [(M+H)⁺].

Example 216(12S,15S,18S)-15-(4-Amino-butyl)-23-(4-aminomethyl-phenyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 216 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 137    -   Boronic Acid Derivative:        (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid

MS (M+H)⁺: expected 809.36; observed 809.7

Example 217(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-(2-methoxypyridin-4-yl)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 114 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h. Suzuki in analogy to Example 189using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.Deprotection: DCM/TFA 1:1, concentrating in vacuo, stirring in water.The title compound was obtained as yellow powder (40 mg). MS ESI (m/z):779.6 [(M+H)⁺].

Example 218(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-morpholino-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 114 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DCM at rt 1 h.

A suspension of tert-butyl3-(((7S,10S,13S)-18-bromo-10-(4-((tert-butoxycarbonyl)amino)butyl)-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecin-13-yl)methyl)-1H-indole-1-carboxylate(30 mg, 28.5 μmol, Eq: 1) in morpholine (143 μl) in a sealed tube washeated to to 70° C. overnight. The reaction mixture was concentrated invacuo and used without further purification.

Deprotection: DCM/TFA 1:1, concentrating in vacuo, stirring in water.The title compound was obtained as orange powder (14 mg). MS ESI (m/z):757.5 [(M+H)⁺].

Example 219(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-24-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione

Example 219 was prepared by BOC-deprotection of intermediate 138.

MS (M+H)⁺: expected 782.22; observed 782.3

Example 220(12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-24-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-1,14,17-trione

Example 220 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 138    -   Boronic Acid Derivative: Phenylboronic acid

MS (M+H)⁺: expected 780.34; observed 780.5

Example 2213-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide

Example 221 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Gln(Trt)-OH.

Tether: Intermediate 111

MS (M+H⁺): expected 795.4; observed 796.4

Example 222(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23hexaene-12,15,18-trione

Example 222 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 121

MS (M+H⁺): expected 799.4; observed 800.3

Example 223(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(2-amino-pyridin-4-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 223 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 122

MS (M+H⁺): expected 796.4; observed 797.7

Example 2244-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-22-yl]-benzenesulfonamide

Example 224 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 123

MS (M+H⁺): expected 859.5; observed 860.7

Example 225(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-22-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 225 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 124

MS (M+H⁺): expected 858.5; observed 859.7

Example 226(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-3-fluoro-12-methyl-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 125 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.4 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Deprotection: DCM/TFA 2:1,concentrating in vacuo, stirring in water. The title compound wasobtained as white powder (39 mg). MS ESI (m/z): 698.6 [(M+H)⁺].

Example 227(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-imidazol-1-yl-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 227 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 126

MS (M+H⁺): expected 770.4; observed 771.2

Example 228(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 228 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 127

MS (M+H⁺): expected 796.4; observed 797.3

Example 2294-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-23-yl]-pyridine-2-carbonitrile

Example 229 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 128

MS (M+H⁺): expected 806.4; observed 807.4

Example 230(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione

Example 230 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 129

MS (M+H⁺): expected 797.4; observed 798.2

Example 2313-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-22-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-11-yl]-propionamide

Example 231 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(Trt)-OH.

Tether: Intermediate 121

MS (M+H⁺): expected 813.4; observed 814.3

Example 232(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(1H-pyrrol-3-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 232 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 130

MS (M+H⁺): expected 769.4; observed 770.3

Example 233(11S,14S,17S)-14-(4-Amino-butyl)-1-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-23-carbonitrile

Example 233 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 107

MS (M+H⁺): expected 743.3; observed 744.3

Example 234(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(4-methanesulfonyl-phenyl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 234 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 102

MS (M+H⁺): expected 872.5; observed 873.3

Example 235 (RO7198462-001-001)4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-23-yl]-benzenesulfonamide

Example 235 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1.        (S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-methyl-1H-indol-3-yl)-propionic        acid,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 119

MS (M+H⁺): expected 873.5; observed 874.3

Example 236(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-3-bromo-12-methyl-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 131 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 3 h. Deprotection: DCM/TFA 2:1,concentrating in vacuo, stirring in water. The title compound wasobtained as white powder (12 mg). MS ESI (m/z): 749.6 [(M+H)⁺].

Example 237(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-17-(dimethylamino)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 132 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Deprotection: DCM/TFA 2:1,concentrating in vacuo, then stirring in water. The title compound wasobtained as light yellow solid (59 mg). MS ESI (m/z): 715.6 [(M+H)⁺].

Example 238(7S,10S,13S)-13-((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-17-(pyridin-3-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione

The material was prepared in analogy to the General Procedure forPeptide Macrocycle Synthesis using the following reagents/conditions:Amino Acids: Fmoc-NMe-L-Trp(Boc)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Orn(Boc)-OH. Reductive Amination: 1.2 eq Intermediate 133 usingNMP/MeOH/AcOH 1:1:0.02 as solvent mixture. Macrocyclization: 1.2 eqHATU, 4 eq DIPEA, in DMF at rt 2 h. Suzuki in analogy to Example 189using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.Deprotection: DCM/TFA 2:1. The title compound was obtained as yellowamorphous solid (6 mg). MS ESI (m/z): 749.4 [(M+H)⁺].

Example 2394-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-benzoicacid

Example 239 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative: 4-(tert-Butoxycarbonyl)phenylboronic        acid

MS (M+H⁺): expected 824.3; observed 825.3

Example 240(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-[4-(2,3-dihydroxy-propoxy)-phenyl]-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 240 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

MS (M+H⁺): expected 870.4; observed 871.4

Example 241{4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-phenoxy}-aceticacid

Example 241 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative: tert-butyl        2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

MS (M+H⁺): expected 8554.3; observed 855.3

Example 242(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-[4-(piperidin-4-yloxy)-phenyl]-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 242 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative: tert-butyl        4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate

MS (M+H⁺): expected 879.4; observed 880.4

Example 243(11S,14S,17S)-14-(4-Amino-butyl)-22-(4-aminomethyl-phenyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 243 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid

MS (M+H⁺): expected 809.4; observed 810.4

Example 244(11S,14S,17S)-14-(4-Amino-butyl)-22-[3-(2-amino-ethyl)-phenyl]-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 244 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        (3-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid

MS (M+H⁺): expected 823.4; observed 824.3

Example 245(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-piperazin-1-yl-phenyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,2-hexaene-12,15,18-trione

Example 245 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        [4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]boronic acid

MS (M+H⁺): expected 864.4; observed 865.4

Example 2464-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide

Example 246 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        [4-(2-hydroxyethylsulfamoyl)phenyl]boronic acid

MS (M+H⁺): expected 903.3; observed 904.3

Example 2474-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzamide

Example 247 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        [4-(2-hydroxyethylcarbamoyl)phenyl]boronic acid

MS (M+H⁺): expected 867.4; observed 868.4

Example 2484-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-dimethylamino-ethyl)-benzamide

Example 248 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        [4-[2-(dimethylamino)ethylcarbamoyl]phenyl]boronic acid;        hydrochloride

MS (M+H⁺): expected 894.4; observed 895.3

Example 2494-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide

Example 249 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        [4-(2-morpholinoethylcarbamoyl)phenyl]boronic acid

MS (M+H⁺): expected 936.4; observed 937.4

Example 250(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-piperidin-4-yl-phenyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 250 was prepared according to the General Procedure for SuzukiCoupling of boronic acid derivatives to Peptide Macrocycle Intermediatesusing the following starting materials:

-   -   Macrocycle Intermediate: Intermediate 140    -   Boronic Acid Derivative:        [4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]boronic acid

MS (M+H⁺): expected 863.4; observed 864.4

Example 251(11S,14S,17S)-11-(3-Amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-14-(4-methylamino-butyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 251 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2.        (S)-6-(tert-Butoxycarbonyl-methyl-amino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic        acid    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H⁺): expected 753.7; observed 753.6

Example 252(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-(3-hydroxy-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 252 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Lys(BOC)—OH,    -   3. Intermediate 141)

Tether: Intermediate 47

TBS Deprotection

The globally-protected macrocyle (110 mg, 0.1 mmol, prepared accordingto general procedures) was mixed with tetrabutylammonium fluoridesolution in THF (1.0 M, 1 mL) and stirred at room temperature for 3hours. The reaction mixture was concentrated and the residue waspurified by silica gel column followed by pre-HPLC (Waters SunFire C18,5 μm, OBD™ 30×100 mm; mobile phase: A, acetonitrile and B, 0.1% TFA inwater) to give the desired macrocyle alcohol (20 mg).

Final BOC-Deprotection

To a solution of macrocyle alcohol obtained above (20 mg, 21 μmol) indichloromethane (500 μl) was added TFA (250 μl). The mixture was stirredat room temperature for 2 hours, and then concentrated in vacuo at roomtemperature. The residue was taken up in −2 ml of water and stirred atroom temperature overnight. MeCN/H2O (v/v=1/1, 1.5 ml) was added and themixture was lyophilized to give the final product (16 mg).

MS (M+H⁺): expected 739.2; observed 740.3

Example 253(11S,14S,17S)-11-(3-Amino-propyl)-14-butyl-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione

Example 253 was prepared according to the General Procedure for PeptideMacrocycle Synthesis using the following starting materials:

-   -   1. Fmoc-NMe-L-Trp(BOC)—OH,    -   2. Fmoc-L-Nle-OH (Fmoc-L-norleucine),    -   3. Fmoc-L-Orn(BOC)—OH.

Tether: Intermediate 47

MS (M+H⁺): expected 723.2; observed 724.3

Example 254 Antimicrobial Susceptibility Testing: Minimum InhibitoryConcentration (MIC) Determination

The in vitro antimicrobial activity of the compounds was determinedthrough microbroth minimum inhibitory concentration (MIC) methodologyperformed according to the Clinical and Laboratory Standard Instituteguidelines (CLSI-M007-A9 January 2012. Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;Approved Standard—Ninth Edition, Clinical and Laboratory StandardsInstitute, Wayne/PA, US and the CLSI-M100-S24 January 2014. PerformanceStandards for Antimicrobial Susceptibility Testing; ApprovedStandard—Fourth Informational Supplement, Clinical and LaboratoryStandards Institute, Wayne/PA, US).

The compound stock solution was freshly prepared at 10× the required topconcentration for the MIC determination, i.e. at 1280 mg/L, byreconstitution of the dry compound in 50:50 water: DMSO.

Polystyrene non-treated 96 wells microtiter plates were used forpreparing panel containing compound serial twofold diluted at two timesthe final testing concentration (e.g. range from 64 to 0.06 μg/ml) incation adjusted Mueller Hinton broth medium (CAMHB).

Inoculum was prepared by the “direct colony suspension method”. Coloniesof A. baumannii ATCC 19606 or clinical isolates were suspended in salinesolution and adjusted to 0.5 McFarland, diluted 100 times in CAMHB brothand 50 μl added to each well (final concentration of cells ˜5×10⁽⁵⁾CFU/ml and Final volume/well of 100 μl). Microtiter plates were sealedand incubated at 35 ±2° C.

MICs values were read after 20 hours of incubation and recorded as thelowest concentration of the antimicrobial that inhibits more or equal to80% of growth of the organism as detected by the unaided eye and using amicrotiter plate optical density reader (OD 600 nm).

Tables 2, 3, 4 and 5 provide the minimum inhibitory concentration (MIC)in microgram per milliliter of the compounds of present inventionobtained against the A. baumannii strain ATCC19606 (Tables 2, 3, 4 and5).

Particular compounds of the present invention exhibit a MIC (ATCC19606)≤64 μg/ml.

More particular compounds of the present invention exhibit a MIC(ATCC19606)≤16 μg/ml.

Most particular compounds of the present invention exhibit a MIC (ATCC19606)≤2 μg/ml.

Example 255 Antimicrobial Susceptibility Testing: 50% Growth InhibitoryConcentration (IC50) Determination

The in vitro antimicrobial activity of the compounds was alternativelydetermined according to the following procedure:

The assay used a 10-points Iso-Sensitest broth medium to measurequantitatively the in vitro activity of the compounds against A.baumannii ATCC 17978.

Stock compounds in DMSO were serially twofold diluted (e.g. range from50 to 0.097 μM final concentration) in 384 wells microtiter plates andinoculated with 49 μl the bacterial suspension in Iso-Sensitest mediumto have a final cell concentration of ˜5×10⁽⁵⁾ CFU/ml in a finalvolume/well of 50 ul/well. Microtiter plates were incubated at 35 ±2° C.

Bacterial cell growth was determined with the measurement of opticaldensity at λ=600 nm each 20 minutes over a time course of 16 h.

Growth inhibition was calculated during the logarithmic growth of thebacterial cells with determination of the concentration inhibiting 50%(IC50) and 90% (IC90) of the growth.

Tables 3, 4 and 5 provide the 50% growth inhibitory concentrations(IC50) in micromoles per liter of the compounds of present inventionobtained against the A. baumannii strain ATCC17978.

Particular compounds of the present invention exhibit an IC50 (ATCC17978)≤10 μmol/l.

More particular compounds of the present invention exhibit an IC50(ATCC17978)≤1 μmol/l.

Most particular compounds of the present invention exhibit an IC50 (ATCC17978)≤0.5 μmol/l.

TABLE 2 Minimum inhibitory concentration (MIC) in microgram permilliliter of the compounds of present invention obtained against A.baumannii strain ATCC19606. ATCC19606 MIC Example [μg/ml] 1 4 2 4 3 16 41 5 32 6 2 7 0.5 8 0.5 9 16 10 2 11 0.5 12 0.5 13 2 14 1 15 32 16 32 1732 18 16 19 16 20 2 21 1 22 32 23 0.5 24 1 25 1 26 1 27 2 28 2 29 2 30 231 1 32 2 33 1 34 16 35 8 36 1 37 2 38 0.5 39 0.5 40 0.5 41 0.5 42 1 431 44 0.5 45 0.5 46 1 47 4 48 2 49 0.5 50 0.25 51 4 52 0.5 53 1 54 1 550.5 56 16 57 0.5 58 0.5 59 0.5 60 2 61 4 62 0.12 63 32 64 32 65 32 660.5 67 0.12 68 0.5 69 4 70 2 71 0.5 72 64 73 1 74 0.25 75 0.12 76 0.1277 0.5 78 0.25 79 0.25 80 0.12 81 1 82 4

TABLE 3 Minimum inhibitory concentration (MIC) in microgram permilliliter of the compounds of present invention obtained against A.baumannii strain ATCC19606 and 50% growth inhibition concentrations(IC50) in micromoles per liter of the compounds of present inventionobtained against A. baumannii strain ATCC17978. ATCC19606 ATCC19606 IC50MIC MIC ATCC17978 Example [μg/ml] Example [μg/ml] [μmol/l] 83 0.5 1178.1 84 0.12 118 0.5 85 0.5 119 4 86 16 120 0.5 87 8 121 2 88 0.25 122 189 0.12 123 1 90 0.25 124 34.9 91 0.5 125 23.3 92 0.5 126 30.3 93 16 12716 94 1 128 2 95 8 129 0.25 96 4 130 1 97 0.12 131 0.25 98 0.12 132 1799 4 133 0.1 100 2 134 2 101 32 135 0.2 102 0.5 136 0.6 103 0.25 137 32104 2 138 0.5 105 1 139 2 106 2 140 0.6 107 8 141 1.3 108 16 142 <0.4109 2 143 <0.4 110 0.5 144 1 111 1 145 4 112 0.5 146 1 113 2 147 0.12114 32 148 8 115 2 149 1 116 8 150 1

TABLE 4 Minimum inhibitory concentration (MIC) in microgram permilliliter of the compounds of present invention obtained against A.baumannii strain ATCC19606 and 50% growth inhibition concentrations(IC50) in micromoles per liter of the compounds of present inventionobtained against A. baumannii strain ATCC17978. ATCC19606 IC50 MICATCC17978 Example [μg/ml] [μmol/l] 151 0.2 152 <0.39 153 <0.39 154 2 1552.7 156 1 157 16 158 <0.39 159 <0.39 160 4 161 6.8 162 0.5 163 4 1640.25 165 4 166 0.5 167 32 168 <0.4 169 4 170 0.5 171 0.5 172 0.5 173 2174 16 175 2 176 5.1 177 1 178 32 179 32 180 1 181 0.25 182 0.5 183 0.25184 2 185 0.5 186 0.5 187 2 188 2 189 4 190 0.12 191 0.12 192 64 193 64194 3.3 195 3 196 0.1 197 0.2 198 0.3 199 1 200 0.12 201 0.4 202 0.12203 1 204 64 205 16 206 1.4 207 9 208 12.5 209 0.25 210 16 211 16 212 32213 2 214 0.25 215 2 216 0.7 217 1 218 2

TABLE 5 Minimum inhibitory concentration (MIC) in microgram permilliliter of the compounds of present invention obtained against A.baumannii strain ATCC19606 and 50% growth inhibition concentrations(IC50) in micromoles per liter of the compounds of present inventionobtained against A. baumannii strain ATCC17978. ATCC19606 IC50 MICATCC17978 Example [μg/ml] [μmol/l] 219 0.6 220 5.8 221 0.25 222 0.12 2231 224 0.12 225 0.12 227 4 228 0.12 229 1 230 0.12 231 1 232 1 233 0.25234 2 235 0.5 236 3.2 237 0.8 238 5.6 239 <1 240 <0.1 241 <0.2 242 <0.2243 <0.1 244 <0.4 245 <0.1 246 <0.1 247 <0.1 248 <0.1 249 <0.1 250 <0.1251 <0.1 252 0.5 253 4.2 226 0.9

The invention claimed is:
 1. A method for the treatment or prevention of infections and resulting diseases caused by Acinetobacter baumannii, which method comprises administering to a human in need thereof a compound according to formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is C-L¹-R¹¹ or N; X² is C-L²-R¹² or N; X³ is C-L³-R¹³ or N; X⁴ is C-L⁴-R¹⁴ or N, with the proviso that not more than three of X¹, X², X³ and X⁴ are N; X⁵ is C-L⁵-R¹⁵ or N; X⁶ is C-L⁶-R¹⁶ or N; X⁷ is C-L⁷ R¹⁷ or N; X⁸ is C-L⁸-R¹⁸ or N, with the proviso that not more than three of X⁵, X⁶, X⁷ and X⁸ are N; R¹ is —(CH₂)_(m)-heteroaryl or —(CH₂)_(m)-heterocycloalkyl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl or C₁₋₇-alkoxy; R², R⁴ and R⁶ are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl; R³ is —C₁₋₇-alkyl, —(CH₂), —NR²⁰R²¹, —(CH₂), —C(O)NR²⁰R²¹ or —(CH₂), —O—(CH₂)_(q)—NR²⁰R²¹; R⁵ is hydrogen, C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³, —(CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)_(o)—O—(CH₂)_(q)—NR²⁰R²¹, —(CH₂)_(o)—NH—C(NH)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—OR²⁶, —(CH₂)_(o)—C₃₋₇-cycloalkyl, —(CH₂)_(o)-heterocycloalkyl, —(CH₂)_(o)-heteroaryl or —(CH₂)_(o)-aryl, wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or aryl; R^(5′) is hydrogen or C₁₋₇-alkyl; R⁷ and R⁸ are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and C₁₋₇-alkoxy; R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are each individually selected from hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy C₁₋₇-alkoxy, haloC₁₋₇-alkoxy, —B(OH)₂, benzyloxy-propynyl (—C≡C—CH₂—O-benzyl), C₃₋₇-cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein heteroaryl is optionally substituted with one C₁₋₇-haloalkyl or C₁₋₇-alkoxy; R¹⁷ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy, B(OH)₂, benzyloxy-prop-1-ynyl, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein heterocycloalkyl is optionally substituted with one —NR²⁴R²⁵, and wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-hydroxyalkyl, hydroxy, C₁₋₇-alkoxy, —NR²⁴R²⁵, SO₂—C₁₋₇-alkyl, —SO₂—NR²⁴R²⁵, heterocycloalkyl and heterocycloalkyl substituted with C₁₋₇-alkyl; R¹⁸ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, hydroxy, C₁₋₇-hydroxyalkyl, C₁₋₇-alkoxy, C₁₋₇-haloalkoxy, —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one, two or three substituents selected from the list of halogen, cyano, C₁₋₇-alkyl C₁₋₇-haloalkyl, hydroxy, C₁₋₇-alkoxy, —NR²⁴-R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, —CO—NH—(CH₂), —NR²⁴R²⁵, —CO—NH—(CH₂), —OH, —CO—NH—(CH₂)_(r)-heterocycloalkyl, —CO—OH, —O—C₁₋₇-hydroxyalkyl, —O—(CH₂)_(r)—CO—OH, —SO₂—C₁₋₇-alkyl, —SO₂—NR²⁴R²⁵, heterocycloalkyl, —O-heterocycloalkyl and heterocycloalkyl substituted with C₁₋₇-alkyl; R²⁰ and R²² are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and —C(═NH)—NH₂; R²¹ and R²³ are each individually selected from hydrogen and C₁₋₇-alkyl; R²⁴ and R²⁵ are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-hydroxyalkyl, and C₃₋₇-cycloalkyl; R²⁶ is hydrogen, C₁₋₇-alkyl or benzyl; L¹, L², L³, L⁴, L⁵, L⁶, L⁷ and L⁸ are each individually selected from a single bond, —C(O)—, —SO₂—, —(CH₂)_(p)—, —CH═CH— and —C≡C—; m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; o is 0, 1, 2, 3, or 4; p is 1, 2, 3, or 4; q is 1, 2, 3, or 4; and r is 1, 2, 3, or
 4. 2. The method of claim 1, wherein the compound has a structure of formula (I′):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is C-L²-R¹¹ or N; X² is C-L²-R¹² or N; X³ is C-L³-R¹³ or N; X⁴ is C-L⁴-R¹⁴ or N, with the proviso that not more than three of X¹, X², X³ and X⁴ are N; X⁵ is C-L⁵-R¹⁵ or N; X⁶ is C-L⁶-R¹⁶ or N; X⁷ is C-L⁷ R′⁷ or N; X⁸ is C-L⁸-R¹⁸ or N, with the proviso that not more than three of X⁵, X⁶, X⁷ and X⁸ are N; R¹ is —(CH₂)_(m)-heteroaryl, wherein heteroaryl is optionally substituted with one or more halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl or C₁₋₇-alkoxy; R², R⁴ and R⁶ are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl; R³ is —(CH₂)_(n)—NR²⁰R²¹; R⁵ is C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³, —(CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³, —(CH₂)_(o)—C₃₋₇-cycloalkyl, —(CH₂)_(o)-heterocycloalkyl, —(CH₂)_(o)-heteroaryl or —(CH₂)_(o)-aryl, wherein cycloalkyl, heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl or C₁₋₇-alkoxy; R⁷ and R⁸ are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and C₁₋₇-alkoxy; R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are each individually selected from hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, haloC₁₋₇-alkoxy, C₃₋₇-cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R²⁰ and R²² are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl and —C(═NH)—NH₂; R²¹ and R²³ are each individually selected from hydrogen and C₁₋₇-alkyl; R²⁴ and R²⁵ are each individually selected from hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl, and C₃₋₇-cycloalkyl; L¹, L², L³, L⁴, L⁵, L⁶, L⁷ and L⁸ are each individually selected from a single bond, —C(O)—, —SO₂—, —(CH₂)_(p)—, —CH═CH— and —C≡C—; and m, n, o and p are each individually selected from 1, 2, 3 and
 4. 3. The method of claim 1, wherein the compound has a structure of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R⁹ is hydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy, C₁₋₇-haloalkoxy or C₃₋₇-cycloalkyl; R¹⁰ is hydrogen, C₁₋₇-alkyl, C₁₋₇-haloalkyl or C₃₋₇-cycloalkyl; R¹⁹ is hydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy, C₁₋₇-haloalkoxy or C₃₋₇-cycloalkyl.
 4. The method of claim 1, wherein the compound has a structure of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R⁹ is hydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇alkoxy, C₁₋₇-haloalkoxy or C₃₋₇-cycloalkyl and Y is —CH₂— or —CO—.
 5. The method of claim 1, wherein the compound has a structure of formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R⁹ is hydrogen, halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇alkoxy, C₁₋₇-haloalkoxy or C₃₋₇-cycloalkyl and Y is —CH₂— or —CO—.
 6. The method of claim 1, wherein R¹ is —(CH₂)_(m)-heteroaryl or —(CH₂)_(m)-heterocycloalkyl, wherein heteroaryl is monocyclic or bicyclic and is optionally substituted with one or more halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₃₋₇-cycloalkyl or C₁₋₇-alkoxy; and wherein heterocycloalkyl is partly unsaturated.
 7. The method of claim 1, wherein R⁵ is hydrogen, C₁₋₇-alkyl, hydroxy-C₁₋₇-alkyl, —(CH₂)_(o)—NR²²R²³, (CH₂)_(o)—C(O)—NR²²R²³, —(CH₂)_(o)—O—(CH₂)_(q)—NR²⁰R²¹, (CH₂)_(o)—NH—C(NH)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—NR²²R²³, —(CH₂)_(o)—NH—C(O)—OR²⁶, —(CH₂)_(o)-heterocycloalkyl, —(CH₂)_(o)-heteroaryl or —(CH₂)_(o)-aryl, and wherein heterocycloalkyl, heteroaryl and aryl are optionally substituted by halo, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, C₁₋₇-alkoxy or aryl.
 8. The method of claim 1, wherein R¹⁵ is hydrogen, halo, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, heterocycloalkyl, aryl or heteroaryl, and wherein heteroaryl is optionally substituted with one C₁₋₇-haloalkyl or C₁₋₇-alkoxy.
 9. The method of claim 1, wherein R¹⁶ is hydrogen, halo, C₁₋₇-alkyl, halo-C₁₋₇-alkyl, heterocycloalkyl or aryl.
 10. The method of claim 1, wherein R¹⁷ is hydrogen, halogen, cyano, C₁₋₇-alkyl, C₁₋₇-haloalkyl, —NR²⁴R²⁵, C₁₋₇-alkyl-NR²⁴R²⁵, hydroxy, C₁₋₇-alkoxy, —B(OH)₂, benzyloxy-propynyl, heterocycloalkyl, aryl or heteroaryl, wherein heterocycloalkyl is optionally substituted with one amino, wherein aryl is optionally substituted with one halo, cyano, —SO₂—C₁₋₇-alkyl, or —SO₂—NR²⁴R²⁵, and wherein heteroaryl is optionally substituted with one or two substituents selected from the list of halogen, cyano, C₁₋₇-alkyl, C₁₋₇-hydroxyalkyl, hydroxy, C₁₋₇-alkoxy, —NR²⁴R²⁵, heterocycloalkyl and heterocycloalkyl substituted with C₁₋₇-alkyl.
 11. The method of claim 1, wherein R¹⁸ is hydrogen, halogen, C₁₋₇-haloalkyl, —NR²⁴R²⁵, heterocycloalkyl, aryl or heteroaryl, wherein aryl is optionally substituted with one substituent selected from the list of C₁₋₇-alkyl-NR²⁴R²⁵, —CO—NH—(CH₂)_(r)—NR²⁴R²⁵, —CO—NH—(CH₂)_(r)—OH, —CO—NH—(CH₂)_(r)-heterocycloalkyl, —CO—OH, —O—C₁₋₇-hydroxyalkyl, —O—(CH₂)_(r)—CO—OH, —SO₂—C₁₋₇-alkyl, —SO₂—NR²⁴R²⁵, heterocycloalkyl, and —O-heterocycloalkyl, and wherein heteroaryl is optionally substituted with one substituent selected from halo, C₁₋₇-alkyl, amino and hydroxy.
 12. The method of claim 1, wherein: X¹ is CR¹¹; X² is CR¹²; X³ is CR¹³; X⁴ is N; X⁵ is CR¹⁵; X⁶ is CR¹⁶ or X⁶ is N; R¹ is —(CH₂)_(m)-indolyl, wherein indolyl is optionally substituted with one or more halo or C₁₋₇-alkyl; R² is hydrogen or C₁₋₇-alkyl; R³ is 3-amino-propyl or 4-amino-butyl; R⁴ is hydrogen; R⁵ is —(CH₂)_(o)—NR²²R²³ or piperidinyl; R⁶ is hydrogen; R⁷ is hydrogen; R⁸ is hydrogen or C₁₋₇-alkyl; R⁹ is hydrogen or C₁₋₇-alkyl; R¹⁰ is hydrogen or C₁₋₇-alkyl; R¹¹ is hydrogen or halo; R¹² is hydrogen or halo; R¹³ is hydrogen; R¹⁴ is hydrogen; R¹⁵ is hydrogen, halo, C₁₋₇-alkyl or halo-C₁₋₇-alkyl; R¹⁶ is hydrogen, halo, C₁₋₇-alkyl or halo-C₁₋₇-alkyl; R¹⁷ is hydrogen, halo, C₁₋₇-alkyl, C₁₋₇-alkoxy or aryl; R¹⁸ is hydrogen, halo or halo-C₁₋₇-alkyl; R¹⁹ is hydrogen or halo; R²⁰ is hydrogen; R²¹ is hydrogen; R²² is hydrogen, C₁₋₇-alkyl or —C(═NH)—NH₂; R²³ is hydrogen; m is 1; n is 3 or 4; and o is 1, 3 or
 4. 13. The method of claim 3, wherein: X¹ is CH or C-halo; X² is CH or C-halo; X³ is CH; X⁴ is CH or N; X⁵ is CH, C-halo, C—C₁₋₇-alkyl or C—C₁₋₇-haloalkyl; X⁶ is N, CH, C-halo, C—C₁₋₇-alkyl or C—C₁₋₇-haloalkyl; X⁷ is CH, C-halo, C—C₁₋₇-alkoxy or C-aryl; X⁸ is CH, C-halo or C—C₁₋₇-haloalkyl; R² is hydrogen or C₁₋₇-alkyl; R³ is 3-amino-propyl or 4-amino-butyl; R⁴ is hydrogen; R⁵ is 3-amino-propyl, 4-methylamino-butyl, guanidinyl-methyl or piperidinyl; R⁶ is hydrogen; R⁷ is hydrogen; R⁸ is hydrogen or C₁₋₇-alkyl; R⁹ is hydrogen or C₁₋₇-alkyl; R¹⁰ is hydrogen or C₁₋₇-alkyl; and R¹⁹ is hydrogen or halo.
 14. The method of claim 1, wherein the compound is selected from the group consisting of: (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12S,15S,18S)-15,18-Bis-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12S,15S,18S)-15-(4-Amino-butyl)-12-(1H-indol-3-ylmethyl)-13-methyl-18-piperidin-4-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; N-[(11S,14S,17S)-14-(4-Amino-butyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-ylmethyl]-guanidine; (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-5,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-5-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(6-chloro-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-methyl-12-(1-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(6-chloro-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(6-chloro-1-methyl-1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (9S,12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-9,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6,7-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-7-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,7-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-7-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-7-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,7-difluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-22-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,23-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11 S,14 S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11 S,14 S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-difluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-6,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-ethyl-12-(1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-6-methoxy-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-13-ethyl-12-(1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-13-ethyl-12-(1H-indol-3-ylmethyl)-4-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-18-(4-methylamino-butyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-6-methoxy-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-methoxy-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16,25-dimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-chloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,13-dimethyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4,6-dichloro-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (9S,12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-9,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-23-methoxy-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-23-fluoro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-fluoro-12-(1H-indol-3-ylmethyl)-4,13-dimethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-ethyl-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-tert-butyl-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-methoxy-13-methyl-12-(2-methyl-1H-indol-3-ylmethyl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-6-isopropyl-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-fluoro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-16-ethyl-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-ethyl-17-(1H-indol-3-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-16-ethyl-17-(1H-indol-3-ylmethyl)-25-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-(3-methyl-3H-imidazol-4-ylmethyl)-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-pyridin-3-ylmethyl-23-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-23-phenyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-17-(1H-indol-3-ylmethyl)-16-methyl-25-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-bromo-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-bromo-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-23,25-bis-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-morpholin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11,16-dimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11-isopropyl-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-hydroxymethyl-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11-isobutyl-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(2-methoxy-pyridin-4-yl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-(S)-1-hydroxy-ethyl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-11,11,16-trimethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-naphthalen-2-ylmethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,7,10,13,16,19-hexaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-7,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-11-naphthalen-1-ylmethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; {(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecahydropyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecin-18-yl}boronic acid; (12 S,15 S,18S)-15-(3-Amino-propyl)-18-biphenyl-4-ylmethyl-12-(1H-indol-3-ylmethyl)-19-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(2-amino-ethoxymethyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-11,14-Bis-(2-amino-ethoxymethyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(2-Amino-ethoxymethyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-trifluoromethyl-2-thia-5,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11R,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11R,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-24-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; 2-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-acetamide; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-4-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrrolidin-1-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(5-fluoro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-quinolin-2-ylmethyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (12S,15S,18S)-15,18-Bis-(3-amino-propyl)-4,6-dichloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(2-methoxy-pyridin-4-yl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23 exaen-11-yl]-propionamde; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(5-chloro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(2,3-dihydro-1H-indol-3-ylmethyl)-16-methyl-22-trifluoromethyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-morpholin-4-yl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,6-dihydro-2H-pyran-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; {3-[(11S,14S,17S)-14-(4-Amino-butyl)-22,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propyarbamic acid benzyl ester; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-6-(2-chloro-phenyl)-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-pyridin-3-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-pyridin-4-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-(1-methyl-1H-pyrazol-3-yl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-methyl-pyridin-4-yl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrazin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-morpholin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridazin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; 11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyridin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15-18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-6-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (8S,11S,14S)-8-((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-1,4-dichloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-3-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-6-(1-methyl-1H-imidazol-4-yl)-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-25-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-11-yl]-propionamide; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-12-methyl-18-(trifluoromethyl)-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-1-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-chloro-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; 3-[(11S,14S,17S)-14-(3-Amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; 3-[(11S,14S,17S)-11-(3-Amino-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-25-trifluoromethyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaen-14-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-morpholin-4-yl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-pyridin-2-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-chloro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(6-dimethylamino-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(2-methylpyridin-4-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-5-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-23-(3,5-dimethyl-isoxazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-methoxy-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-23-(5-methanesulfonyl-pyridin-3-yl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(3-amino-pyrrolidin-1-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,5-dimethyl-1H-pyrazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-5-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (7S,10S,13 S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(6-methylpyridin-3-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-3-chloro-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; [(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-ylmethyl]-urea; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-23-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-chloro-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2-fluoro-pyridin-4-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-23-phenyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-23-carbonitrile; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(3,5-dimethyl-isoxazol-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(3-benzyloxy-prop-1-ynyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-phenyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-9-methyl-2-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-9-methyl-4-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[3,4-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(pyridin-3-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(pyridin-4-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-1-(2-methoxypyridin-4-yl)-9-methyl-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-bromo-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-(2-(trifluoromethyl)pyridin-4-yl)-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(5-methanesulfonyl-pyridin-3-yl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (8S,11S,14S)-8((1H-Indol-3-yl)methyl)-11-(4-aminobutyl)-14-(3-aminopropyl)-4-chloro-9-methyl-1-morpholino-5,6,8,9,11,12,15,16-octahydrobenzo[b]pyrido[4,3-p][1,5,8,11,14]thiatetraazacycloheptadecine-7,10,13(14H)-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-22-pyridin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-20-chloro-6,7,9,10,12,13,15,16-octahydro-12-methyl-13-[(2-methyl-1H-indol-3-yl)methyl]-18-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]pyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecine-8,11,14(5H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-morpholino-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-(2-methoxypyridin-4-yl)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:4′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-23-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-23-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-23-pyridin-3-yl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(2,6-difluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3(8),4,6,22,24-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-N-methyl-propionamide; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-23-yl]-benzonitrile; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(2-methyl-pyridin-4-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-pyrimidin-4-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-23-yl]-benzenesulfonamide; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-(2-methylpyridin-4-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (12S,15S,18S)-15-(4-Amino-butyl)-23-(4-aminomethyl-phenyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-18-(2-methoxypyridin-4-yl)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-18-morpholino-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:2′,3′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (12 S,15 S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-24-bromo-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; (12S,15S,18S)-15-(4-Amino-butyl)-18-(3-amino-propyl)-4-chloro-12-(1H-indol-3-ylmethyl)-13-methyl-24-phenyl-2-thia-10,13,16,19-tetraaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3,5,7,21,23-hexaene-11,14,17-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-22-pyridin-3-yl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-23-(2-amino-pyridin-4-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-22-yl]-benzenesulfonamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-22-(4-methanesulfonyl-phenyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-3-fluoro-12-methyl-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-imidazol-1-yl-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-22-(6-amino-pyridin-3-yl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-23-yl]-pyridine-2-carbonitrile; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-(6-hydroxy-pyridin-3-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaene-12,15,18-trione; 3-[(11S,14S,17S)-14-(4-Amino-butyl)-25-chloro-22-(2-fluoro-pyridin-4-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(21),3,5,7,22,24-hexaen-11-yl]-propionamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-23-(1H-pyrrol-3-yl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-23-carbonitrile; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-23-(4-methanesulfonyl-phenyl)-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-16-methyl-17-(2-methyl-1H-indol-3-ylmethyl)-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-23-yl]-benzenesulfonamide; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-3-bromo-12-methyl-6,7,9,10,12,13,15,16-octahydrobenzo[b]pyrido[3,2-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-17-(dimethylamino)-12-methyl-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; (7S,10S,13S)-13((1H-Indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-17-(pyridin-3-yl)-6,7,9,10,12,13,15,16-octahydrodipyrido[2,3-b:3′,4′-p][1,5,8,11,14]thiatetraazacycloheptadecine-8,11,14(5H)-trione; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-benzoic acid; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-22-[4-(2,3-dihydroxy-propoxy)-phenyl]-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; {4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-phenoxy}-acetic acid; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-[4-(piperidin-4-yloxy)-phenyl]-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-22-(4-aminomethyl-phenyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-22-[3-(2-amino-ethyl)-phenyl]-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-piperazin-1-yl-phenyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-hydroxy-ethyl)-benzamide; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-dimethylamino-ethyl)-benzamide; 4-[(11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; (11S,14S,17S)-14-(4-Amino-butyl)-11-(3-amino-propyl)-25-chloro-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-piperidin-4-yl-phenyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-11-(3-Amino-propyl)-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-14-(4-methylamino-butyl)-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; (11S,14S,17S)-14-(4-Amino-butyl)-23,25-dichloro-11-(3-hydroxy-propyl)-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; and (11S,14S,17S)-11-(3-Amino-propyl)-14-butyl-23,25-dichloro-17-(1H-indol-3-ylmethyl)-16-methyl-2-thia-4,10,13,16,19-pentaaza-tricyclo[19.4.0.0*3,8*]pentacosa-1(25),3(8),4,6,21,23-hexaene-12,15,18-trione; or a pharmaceutically acceptable salt thereof.
 15. The method of claim 1, wherein the disease or diseases are selected from the group consisting of bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.
 16. The method of claim 14, wherein the disease or diseases are selected from the group consisting of bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection. 